1h-pyrazolo[4,3-b]pyridines as pde1 inhibitors

ABSTRACT

The present invention provides 1H-pyrazolo[4,3-b]pyridin-7-amines of formula (1) as PDE1 inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention claims priority to Danish Patent Applications No.PA 2016 00397 (filed on Jul. 4, 2016), PA 2016 00612 (filed on Oct. 11,2016), and PA 2017 00236 (filed on Apr. 4, 2017), each of whichapplications is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention provides compounds that are PDE1 enzyme inhibitorsand their use as a medicament, in particular for the treatment ofneurodegenerative disorders and psychiatric disorders. The presentinvention also provides pharmaceutical compositions comprising compoundsof the invention and methods of treating disorders using the compoundsof the invention.

BACKGROUND OF THE INVENTION

Throughout this application, various publications are referenced infull. The disclosures of these publications are hereby incorporated byreference into this application to describe more fully the state of theart to which this invention pertains.

The second messenger cyclic Nucleotides (cNs), cyclic adenosinemonophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play amajor role in intracellular signal transduction cascade, by regulatingcN-dependent protein kinases (PKA and PKG), EPACs (Exchange ProteinActivated by cAMP), phosphoprotein phosphatases, and/or cN-gated cationchannels. In neurons, this includes the activation of cAMP- andcGMP-dependent kinases and subsequent phosphorylation of proteinsinvolved in acute regulation of synaptic transmission as well as inneuronal differentiation and survival. Intracellular concentrations ofcAMP and cGMP are strictly regulated by the rate of biosynthesis bycyclases and by the rate of degradation by phosphodiesterases (PDEs, EC3.1.4.17). PDEs are bimetallic hydrolases that inactivate cAMP/cGMP bycatalytic hydrolysis of the 3′-ester bond, forming the inactive5′-monophosphate. Since PDEs provide the only means of degrading thecyclic nucleotides cAMP and cGMP in cells, PDEs play an essential rolein cyclic nucleotide signalling. The catalytic activities of PDEsprovide for breakdown of cNs over a spectrum of cN-concentrations in allcells, and their varied regulatory mechanisms provide for integrationand crosstalk with myriads of signalling pathways. Particular PDEs aretargeted to discrete compartments within cells where they control cNlevel and sculpt microenvironments for a variety of cN signalosomes(Sharron H. Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev2011, 91: 651-690).

On the basis of substrate specificity, the PDE families can be dividedinto three groups: 1) The cAMP-specific PDEs, which include PDE4, PDE7,and PDE8, 2) the cGMP-selective enzymes PDE5 and PDE9, and 3) thedual-substrate PDEs, PDE1, PDE2, PDE3, as well as PDE10 and PDE11.

Previously named calmodulin-stimulated PDE (CaM-PDE), PDE1 is unique inthat it is Ca²⁺-dependently regulated via calmodulin (CaM, a 16 kDaCa²⁺-binding protein) complexed with four Ca²⁺ (for review, Sharron H.Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev 2011, 91:651-690). Thus, PDE1 represents an interesting regulatory link betweencyclic nucleotides and intracellular Ca²⁺. The PDE1 family is encoded bythree genes: PDE1A (mapped on human chromosome 2q32), PDE1B (humanchromosome location, hcl: 12q13) and PDE1C (hcl: 7p14.3). They havealternative promoters and give rise to a multitude of proteins byalternative splicing which differ in their regulatory properties,substrate affinities, specific activities, activation constants for CaM,tissue distribution and molecular weights. More than 10 human isoformsare identified. Their molecular weights vary from 58 to 86 kDa permonomer. The N-terminal regulatory domain that contains two Ca²⁺/CaMbinding domains and two phosphorylation sites differentiate theircorresponding proteins and modulate their biochemical functions. PDE1 isa dual substrate PDE and the PDE1C-subtype has equal activity towardscAMP and cGMP (Km≈1-3 μM), whereas the subtypes PDE1A and PDE1B have apreference for cGMP (Km for cGMP≈1-3 μM and for cAMP≈10-30 μM).

The PDE1 subtypes are highly enriched in the brain and locatedespecially in the striatum (PDE1B), hippocampus (PDE1A) and cortex(PDE1A) and this localization is conserved across species (Amy Bernardet al. Neuron 2012, 73, 1083-1099). In the cortex, PDE1A is presentmainly in deep cortical layers 5 and 6 (output layers), and used as aspecificity marker for the deep cortical layers. PDE1 inhibitors enhancethe levels of the second messenger cNs leading to enhanced neuronalexcitability.

Thus, PDE1 is a therapeutic target for regulation of intracellularsignalling pathways, preferably in the nervous system and PDE1inhibitors can enhance the levels of the second messengers cAMP/cGMPleading to modulation of neuronal processes and to the expression ofneuronal plasticity-related genes, neurotrophic factors, andneuroprotective molecules. These neuronal plasticity enhancementproperties together with the modulation of synaptic transmission makePDE1 inhibitors good candidates as therapeutic agents in manyneurological and psychiatric conditions. The evaluation of PDE1inhibitors in animal models (for reviews see e.g. Blokland et al. ExpertOpinion on Therapeutic Patents (2012), 22(4), 349-354; and Medina, A. E.Frontiers in Neuropharmacology (2011), 5(February), 21) has suggestedthe potential for the therapeutic use of PDE1 inhibitors in neurologicaldisorders, like e.g. Alzheimer's, Parkinson's and Huntington's Diseasesand in psychiatric disorders like e.g. Attention Deficit hyperactivityDisorder (ADHD), depression, anxiety, narcolepsy, cognitive impairmentand cognitive impairment associated with schizophrenia (CIAS) and inrestless leg syndrome. There have also been patent applications claimingthat PDE1 inhibitors are useful in diseases that may be alleviated bythe enhancement of progesterone-signalling such as female sexualdysfunction (e.g. WO 2008/070095).

The compounds of the invention may offer alternatives to currentmarketed treatments for neurodegenerative and/or psychiatric disorders,treatments which are not efficacious in all patients. Hence, thereremains a need for alternative methods of treatment of such diseases.

SUMMARY OF THE INVENTION

PDE1 enzymes are expressed in the Central Nervous System (CNS), makingthis gene family an attractive source of new targets for the treatmentof psychiatric and neurodegenerative disorders.

Accordingly, the present invention relates to compounds of formula (I)

whereinL is selected from the group consisting of NH, CH₂, S and O;R1 is selected from the group consisting of hydrogen, linear or branchedC₁-C₅ alkyl, C₁-C₅ fluoroalkyl and saturated monocyclic C₃-C₅cycloalkyl;R2 is selected from the group consisting of linear or branched C₁-C₈alkyl, saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl,tetrahydrofuranyl, and tetrahydropyranyl; all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of methyl, fluorine, hydroxy, cyano andmethoxy;R3 is methyl substituted with phenyl, pyridonyl, pyridinyl, pyrimidinylor pyrazinyl all of which can be optionally substituted one or moretimes with one or more substituents selected from the group consistingof halogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxyand C₁-C₃ alkoxy; orR3 is methyl substituted with a 5-membered heteroaryl which isoptionally substituted with one or more substituents selected fromhalogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxy andC₁-C₃ alkoxy; orR3 is ethyl substituted with phenyl, pyridonyl, pyridinyl, pyrimidinylor pyrazinyl all of which can be optionally substituted one or moretimes with one or more substituents selected from the group consistingof halogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₅ fluoroalkoxyand C₁-C₃ alkoxy; orR3 is ethyl substituted with a 5-membered heteroaryl which is optionallysubstituted with one or more substituents selected from halogen, cyano.C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxy and C₁-C₃ alkoxy; orL is CH₂ and R3 is NH which is substituted with phenyl, pyridonyl,pyridinyl, pyrimidinyl or pyrazinyl all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of halogen, cyano, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ fluoroalkoxy and C₁-C₃ alkoxy; orL is CH₂ and R3 is NH which is substituted with a 5-membered heteroarylwhich is optionally substituted with one or more substituents selectedfrom halogen, cyano. C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₅ fluoroalkoxyand C₁-C₃ alkoxy;R4 is phenyl, pyridinyl or pyridonyl all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄fluoroalkyl, C₁-C₄ deutereoalkyl, C₁-C₃ fluoroalkoxy, cyclopropyloxy,C₁-C₃ alkoxy, C₁-C₃ deutereoalkoxy and —N—R5R6 wherein R5 and R6 areeach independently selected from H, C₁-C₃ alkyl and C₁-C₃ deutereoalkyl;orR4 is a 5-membered heteroaryl which is optionally substituted with oneor more substituents selected from halogen, cyano, C₁-C₄ alkyl, C₁-C₄fluoroalkyl, C₁-C₄ deutereoalkyl, C₁-C₃ fluoroalkoxy, cyclopropyloxy,C₁-C₃ alkoxy, C₁-C₃ deutereoalkoxy and —N—R5R6 wherein R5 and R6 areeach independently selected from H, C₁-C₃ alkyl and C₁-C₃ deutereoalkyl;orR4 is a 4, 5 or 6 membered saturated heterocycle all of which can beoptionally substituted with one or more substituents selected from oxo,C₁-C₄ alkyl and C₁-C₄ fluoroalkyl;and pharmaceutically acceptable salts thereof.

Reference to Compound I includes the free base of Compound I,pharmaceutically acceptable salts of Compound I, such as acid additionsalts of Compound I, racemic mixtures of Compound I, or thecorresponding enantiomer and/or optical isomer of Compound I, andpolymorphic and amorphous forms of Compound I as well as tautomericforms of Compound I. Furthermore, the compounds of this invention mayexist in unsolvated as well as in solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol and the like. In general, thesolvated forms are considered equivalent to the unsolvated forms for thepurposes of this invention.

In one embodiment, the invention relates to a compound according toformula (I) for use in therapy.

In one embodiment, the invention relates to a pharmaceutical compositioncomprising a compound according formula (I), and one or morepharmaceutically acceptable carrier or excipients.

In one embodiment, the invention relates to a compound according toformula (I), for use in the treatment of a neurodegenerative disorder,selected from the group consisting of Alzheimers Disease, Parkinson'sDisease and Huntington's Disease or for the treatment of a psychiatricdisorder such as Attention Deficit hyperactivity Disorder (ADHD),depression, anxiety, narcolepsy, cognitive impairment and cognitiveimpairment associated with schizophrenia (CIAS), or another braindisease like restless leg syndrome.

In one embodiment, the invention relates to a method for the treatmentof a neurodegenerative disorder, selected from the group consisting ofAlzheimer's Disease, Parkinson's Disease and Huntington's Disease or forthe treatment of a psychiatric disorder such as Attention Deficithyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,cognitive impairment and cognitive impairment associated withschizophrenia (CIAS), or another brain disease like restless legsyndrome, which method comprises the administration of a therapeuticallyeffective amount of a compound according to formula (I) to a patient inneed thereof.

In one embodiment, the invention relates to the use of a compoundaccording to formula (I), for the manufacture of a medicament for thetreatment of a neurodegenerative disorder, selected from the groupconsisting of Alzheimer's Disease, Parkinson's Disease and Huntington'sDisease or for the treatment of a psychiatric disorder such as AttentionDeficit hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,cognitive impairment and cognitive impairment associated withschizophrenia (CIAS), or another brain disease like restless legsyndrome.

Definitions PDE1 Enzymes:

The PDE1 isozyme family includes numerous splice variant PDE1 isoforms.It has three subtypes, PDE1A, PDE1B and PDE1C which divide further intovarious isoforms. In the context of the present invention PDE1 and PDE1enzymes are synonymous and refer to PDE1A, PDE1B and PDE1C enzymes aswell as their isoforms unless otherwise specified.

PDE1 Inhibitors:

In the context of the present invention, a compound is considered to bea PDE1 inhibitor if the amount required to reach the IC₅₀ level of anyof the three PDE1 isoforms is 10 micro molar or less, preferably lessthan 9 micro molar, such as 8 micro molar or less, such as 7 micro molaror less, such as 6 micro molar or less, such as 5 micro molar or less,such as 4 micro molar or less, such as 3 micro molar or less, morepreferably 2 micro molar or less, such as 1 micro molar or less, inparticular 500 nM or less.

In general, compounds of the invention exhibits selectivity towards thePDE1B isoform meaning that said compounds are stronger as PDE1Binhibitors than as PDE1A and/or PDE1C inhibitors. In preferredembodiments, said compounds are at least two fold stronger, five-foldstronger or ten-fold stronger as PDE1B inhibitors than as PDE1A and/orPDE1C inhibitors. In more preferred embodiments, said compounds are atleast fifteen-fold stronger or twenty-fold stronger as PDE1B inhibitorsthan as PDE1A and/or PDE1C inhibitors.

In preferred embodiments the required amount of PDE1 inhibitor requiredto reach the IC₅₀ level of PDE1B is 400 nM or less, such as 300 nM orless, 200 nM or less, 100 nM or less, or even 80 nM or less, such as 50nM or less, for example 25 nM or less. Selectivity towards the PDE1Bisoform may prevent potentially unwanted effects associated with PDE1Aand/or PDE1C inhibition. For example potentially unwanted peripheraleffects.

Substituents:

In the present context, “optionally substituted” means that theindicated moiety may or may not be substituted, and when substituted ismono-, di-, or tri-substituted. It is understood that where nosubstituents are indicated for an “optionally substituted” moiety, thenthe position is held by a hydrogen atom.

As used in the context of the present invention, the terms “halo” and“halogen” are used interchangeably and refer to fluorine, chlorine,bromine or iodine.

A given range may interchangeably be indicated with “-” (dash) or “to”,e.g. the term “C₁-C₃ alkyl” is equivalent to “C₁ to C alkyl”.

The terms “C₁-C₃ alkyl”, “C₁-C₄ alkyl”, “C₁-C₅ alkyl”, “C₁-C₈ alkyl”,“C₁-C₇ alkyl” and “C₁-C₈ alkyl” refer to a linear (i.e. unbranched) orbranched saturated hydrocarbon having from one up to eight carbon atoms,inclusive. Examples of such groups include, but are not limited to,methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl,2-methyl-1-butyl, n-hexyl, n-heptyl and n-octyl.

The term “C₁-C₃ fluoroalkyl” refers to a C₁-C₃ alkyl substituted withone or more fluorine.

The terms, “C₁-C₄ deutereoalkyl” and “C₁-C₃ deutereoalkyl” refer to aC₁-C₄ alkyl and a C₁-C₃ alkyl wherein one or more hydrogen atoms aredesignated as deuterium. Examples of “C₁-C₃ deutereoalkyl” include, butare not limited to, trideuteriomethyl, 1,1-dideuterioethyl,2,2,2-trideuterioethyl and 1,1,2,2,2-pentadeuterioethyl.

The term saturated monocyclic C₃-C₈ cycloalkyl refers to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycooctyl.

The term “5-membered heteroaryl” refers to a 5 membered aromaticmonocyclic ring containing 1 to 4 carbon atoms and one or moreheteroatoms selected from oxygen, nitrogen and sulfur. Examples include,but are not limited to thiazolyl, oxazolyl, isoxazolyl, triazolyl,pyrazolyl, tetrazolyl, imidazolyl, oxadiazolyl and thiadiazolyl andthiophenyl.

The term “C₁-C₃ alkoxy” refers to a moiety of the formula —OR′, whereinR′ indicates C₁-C₃ alkyl as defined above.

The term “C₁-C₃ fluoroalkoxy” refers to a moiety of the formula —OR′,wherein R′ indicates C₁-C₃ fluoroalkyl as defined above.

The term, “C₁-C₃ deutereoalkoxy” refers to a C₁-C₃ alkoxy wherein one ormore hydrogen atoms are designated as deuterium. Examples include, butare not limited to, trideuteriomethoxy, 1,1-dideuteroethoxy,2,2,2-trideuterioethoxy and 1,1,2,2,2-pentadeuterioethoxy.

The terms “4, 5 or 6 membered saturated heterocycle” refers to asaturated monocyclic ring containing 1 to 3, 4, or 5 carbon atoms andone or more heteroatoms selected from oxygen, nitrogen and sulfur,Examples include, but are not limited to oxazolidin-2-one,azetidin-2-one, imidazolidin-2-one, pyrrolidin-2-one,imidazolidine-2,4-dione, oxazolidine-2,4-dione or piperidin-2-one.

Isomeric and Tautomeric Forms:

Where compounds of the present invention contain one or more chiralcenters reference to any of the compounds will, unless otherwisespecified, cover the enantiomerically or diastereomerically purecompound as well as mixtures of the enantiomers or diastereomers in anyratio. For example, compound Example 15 is prepared as a racemate andcovers both(R)-5-(2-ethoxypyridin-3-yl)-1-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand(S)-5-(2-ethoxypyridin-3-yl)-1-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-7-amineas well as mixtures of these two enantiomers in any ratio, including theracemic mixture. The R-enantiomer of compound Example 15 has beendesignated as “15a” while the S-enantiomer has been designated as “15b”.

When a compound of the invention is denoted with the suffix “enantiomer1” or “enantiomer 2” it is understood that said enantiomer could beeither the S-enantiomer or the R-enantiomer. I.e. “enantiomer 1” couldbe either the S-enantiomer or the R-enantiomer and “enantiomer 2” couldbe either the S-enantiomer or the R-enantiomer. When both enantiomer 1and enantiomer 2 have been exemplified for a compound it follows thatone is the S-enantiomer and the other is the R-enantiomer. For examplecompound Example 123 is5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1; and compound Example 124 is5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2. It follows that if for example compound Example 123 can bedetermined to be the R-enantiomer, then compound Example 124 will be theS-enantiomer and vice versa.

Some compounds of the invention have been exemplified in only oneenantiomeric form, like for example compound Example 125:5-(2-ethoxy-3-pyridyl)-N-[(5-methoxy-3-pyridyl)methyl]-3-methyl-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2, which has been prepared from1-(sec-buty)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2. In such case it follows that the corresponding enantiomer(“enantiomer 1”) can be prepared by a similar method from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1. Thus, the corresponding enantiomer (“enantiomer 1”) isalso a compound of the invention that can be individually claimed.Example 125 thus covers both enantiomeric forms, which can each beindividually claimed, although only “enantiomer 2” has been prepared andtested in the PDE1 assay. The R-enantiomer of compound Example 125 hasbeen designated as “125a” while the S-enantiomer has been designated as“125b”. The same principle applies for other exemplified compounds forwhich only one enantiomer has been prepared.

The absolute stereochemistry for a compound of the invention can bedetermined by X-ray crystallography or vibrational circular dichroism.

Furthermore, some of the compounds of the present invention may exist indifferent tautomeric forms and it is intended that any tautomeric formsthat the compounds are able to form are included within the scope of thepresent invention.

Deuterated Compounds:

The present invention also comprises deuterated compounds. The term“deuterated compound” indicates a compound comprising one or more atomsthat are designated as deuterium.

It is recognized that elements are present in natural isotopicabundances in most synthetic compounds, and result in inherentincorporation of deuterium. The natural isotopic abundance of hydrogenisotopes such as deuterium is about 0.015%. Thus, as used herein,designation of an atom as deuterium at a position indicates that theabundance of deuterium is significantly greater than the naturalabundance of deuterium. Any atom not designated as a particular isotopeis intended to represent any stable isotope of that atom, as will beapparent to the ordinarily skilled artisan. Any atom not designated asdeuterium is present at about its natural isotopic abundance.

In some embodiments, designation of a position as “D” in a compound hasa minimum deuterium incorporation of greater than 50% at that position.In some embodiments, designation of a position as “D” in a compound hasa minimum deuterium incorporation of greater than 60%, such as greaterthan 65%, such as greater than 70%, such as greater than 75%, such asgreater than 80% at that position. In a preferred embodiment,designation of a position as “D” in a compound has a minimum deuteriumincorporation of greater than 85%, such as greater than 90% at thatposition. In a more preferred embodiment, designation of a position as“D” in a compound has a minimum deuterium incorporation of greater than95%, such as greater than 97%, such as greater than 99% at thatposition.

The deuterated compounds of the present invention are compounds whereinone or more atoms of the substituent in R4 position are designated adeuterium.

Pharmaceutically Acceptable Salts:

The compounds of this invention are generally utilized as the freesubstance or as a pharmaceutically acceptable salt thereof. When acompound of formula (I) contains a free base such salts are prepared ina conventional manner by treating a solution or suspension of a freebase of formula (I) with a molar equivalent of a pharmaceuticallyacceptable acid. Representative examples of suitable organic andinorganic acids are described below.

Pharmaceutically acceptable salts in the present context is intended toindicate non-toxic, i.e. physiologically acceptable salts. The termpharmaceutically acceptable salts includes salts formed with inorganicand/or organic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, nitrous acid, sulphuric acid, benzoic acid, citricacid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaricacid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaricacid, glutamic acid, pyroglutamic acid, salicylic acid, salicylic acid,saccharin and sulfonic acids, such as methanesulfonic acid,ethanesulfonic acid, toluenesulfonic acid and benzenesulfonic acid. Someof the acids listed above are di- or tri-acids, i.e. acids containingtwo or three acidic hydrogens, such as phosphoric acid, sulphuric acid,fumaric acid and maleic acid.

Additional examples of useful acids and bases to form pharmaceuticallyacceptable salts can be found e.g. in Stahl and Wermuth (Eds) “Handbookof Pharmaceutical salts. Properties, selection, and use”. Wiley-VCH,2008.

Therapeutically Effective Amount:

In the present context, the term “therapeutically effective amount” of acompound means an amount sufficient to cure, alleviate or partiallyarrest the clinical manifestations of a given disease and itscomplications in a therapeutic intervention comprising theadministration of said compound. An amount adequate to accomplish thisis defined as “therapeutically effective amount”. Effective amounts foreach purpose will depend on the severity of the disease or injury aswell as the weight and general state of the subject. It will beunderstood that determining an appropriate dosage may be achieved usingroutine experimentation, by constructing a matrix of values and testingdifferent points in the matrix, which is all within the ordinary skillsof a trained physician.

Treatment and Treating:

In the present context, “treatment” or “treating” is intended toindicate the management and care of a patient for the purpose ofalleviating, arresting, partly arresting or delaying progress of theclinical manifestation of the disease, or curing the disease. Thepatient to be treated is preferably a mammal, in particular a humanbeing.

Administration Routes:

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,buccal, sublingual, transdermal and parenteral (e.g. subcutaneous,intramuscular, and intravenous) route; the oral route being preferred.

It will be appreciated that the route will depend on the generalcondition and age of the subject to be treated, the nature of thecondition to be treated and the active ingredient.

Pharmaceutical Formulations and Excipients:

In the following, the term, “excipient” or “pharmaceutically acceptableexcipient” refers to pharmaceutical excipients including, but notlimited to, fillers, antiadherents, binders, coatings, colours,disintegrants, flavours, glidants, lubricants, preservatives, sorbents,sweeteners, solvents, vehicles and adjuvants.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), such as one of the compoundsdisclosed in the Experimental Section herein. The present invention alsoprovides a process for making a pharmaceutical composition comprising acompound of formula (I). The pharmaceutical compositions according tothe invention may be formulated with pharmaceutically acceptableexcipients in accordance with conventional techniques such as thosedisclosed in Remington, “The Science and Practice of Pharmacy”, 22^(th)edition (2012), Edited by Allen, Loyd V., Jr.

Pharmaceutical compositions for oral administration include solid oraldosage forms such as tablets, capsules, powders and granules; and liquidoral dosage forms such as solutions, emulsions, suspensions and syrupsas well as powders and granules to be dissolved or suspended in anappropriate liquid.

Solid oral dosage forms may be presented as discrete units (e.g. tabletsor hard or soft capsules), each containing a predetermined amount of theactive ingredient, and preferably one or more suitable excipients. Whereappropriate, the solid dosage forms may be prepared with coatings suchas enteric coatings or they may be formulated so as to provide modifiedrelease of the active ingredient such as delayed or extended releaseaccording to methods well known in the art. Where appropriate, the soliddosage form may be a dosage form disintegrating in the saliva, such asfor example an orodispersible tablet.

Examples of excipients suitable for solid oral formulation include, butare not limited to, microcrystalline cellulose, corn starch, lactose,mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin,talcum, gelatin, pectin, magnesium stearate, stearic acid and loweralkyl ethers of cellulose. Similarly, the solid formulation may includeexcipients for delayed or extended release formulations known in theart, such as glyceryl monostearate or hypromellose. If solid material isused for oral administration, the formulation may for example beprepared by mixing the active ingredient with solid excipients andsubsequently compressing the mixture in a conventional tabletingmachine; or the formulation may for example be placed in a hard capsulee.g. in powder, pellet or mini tablet form. The amount of solidexcipient will vary widely but will typically range from about 25 mg toabout 1 g per dosage unit.

Liquid oral dosage forms may be presented as for example elixirs,syrups, oral drops or a liquid filled capsule. Liquid oral dosage formsmay also be presented as powders for a solution or suspension in anaqueous or non-aqueous liquid. Examples of excipients suitable forliquid oral formulation include, but are not limited to, ethanol,propylene glycol, glycerol, polyethyleneglycols, poloxamers, sorbitol,poly-sorbate, mono and di-glycerides, cyclodextrins, coconut oil, palmoil, and water. Liquid oral dosage forms may for example be prepared bydissolving or suspending the active ingredient in an aqueous ornon-aqueous liquid, or by incorporating the active ingredient into anoil-in-water or water-in-oil liquid emulsion.

Further excipients may be used in solid and liquid oral formulations,such as colourings, flavourings and preservatives etc.

Pharmaceutical compositions for parenteral administration includesterile aqueous and nonaqueous solutions, dispersions, suspensions oremulsions for injection or infusion, concentrates for injection orinfusion as well as sterile powders to be reconstituted in sterilesolutions or dispersions for injection or infusion prior to use.Examples of excipients suitable for parenteral formulation include, butare not limited to water, coconut oil, palm oil and solutions ofcyclodextrins. Aqueous formulations should be suitably buffered ifnecessary and rendered isotonic with sufficient saline or glucose.

Other types of pharmaceutical compositions include suppositories,inhalants, creams, gels, dermal patches, implants and formulations forbuccal or sublingual administration.

It is requisite that the excipients used for any pharmaceuticalformulation comply with the intended route of administration and arecompatible with the active ingredients.

Doses:

In one embodiment, the compound of the present invention is administeredin an amount from about 0.001 mg/kg body weight to about 100 mg/kg bodyweight per day. In particular, daily dosages may be in the range of 0.01mg/kg body weight to about 50 mg/kg body weight per day. The exactdosages will depend upon the frequency and mode of administration, thesex, the age, the weight, and the general condition of the subject to betreated, the nature and the severity of the condition to be treated, anyconcomitant diseases to be treated, the desired effect of the treatmentand other factors known to those skilled in the art.

A typical oral dosage for adults will be in the range of 0.1-1000 mg/dayof a compound of the present invention, such as 1-500 mg/day, such as1-100 mg/day or 1-50 mg/day. Conveniently, the compounds of theinvention are administered in a unit dosage form containing saidcompounds in an amount of about 0.1 to 500 mg, such as 10 mg, 50 mg 100mg, 150 mg, 200 mg or 250 mg of a compound of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have identified compounds that are PDE1inhibitors, and as such are useful to treat neurodegenerative andpsychiatric disorders. The present invention thus provides compounds offormula (I) that are effective in inhibiting PDE1 for use as amedicament in the treatment of a mammal, preferably a human.

The invention provides a compound of formula (I) or a pharmaceuticallyacceptable acid addition salt thereof, as well as a pharmaceuticalcomposition containing such a compound, for use in the treatment of abrain disease which could be a neurodegenerative disorder or apsychiatric disorder. In a preferred embodiment the neurodegenerativedisorder is selected from the group consisting of Alzheimer's Disease,Parkinson's Disease and Huntington's Disease. In another preferredembodiment the psychiatric disorder is selected from the groupconsisting of Attention Deficit hyperactivity Disorder (ADHD),depression, anxiety, narcolepsy, cognitive impairment and cognitiveimpairment associated with schizophrenia (CIAS). Other brain disorderscould be e.g. restless leg syndrome.

This invention further provides a method of treating a brain diseasewhich could be a neurodegenerative or a psychiatric disorder, whichmethod comprises administering to said mammal a pharmaceuticallyeffective amount of a compound of formula (I). Examples ofneurodegenerative disorders that can be treated according to the presentinvention include Alzheimer's Disease, Parkinson's Disease andHuntington's Disease, which method comprises administering to thesubject a therapeutically effective amount of a compound of formula (I).Examples of psychiatric disorders that can be treated according to thepresent invention include Attention Deficit hyperactivity Disorder(ADHD), depression, narcolepsy, cognitive impairment and cognitiveimpairment associated with schizophrenia (CIAS). Other brain disordersto be treated could be e.g. restless leg syndrome.

EMBODIMENTS OF THE INVENTION

In the following, embodiments of the invention are disclosed. The firstembodiment is denoted E1, the second embodiment is denoted E2 and soforth

In a first embodiment E1 the present invention relates to compounds offormula (I)

E1. A compound according to formula (I)

whereinL is selected from the group consisting of NH, CH₂, S and O;R1 is selected from the group consisting of hydrogen, linear or branchedC₁-C₅ alkyl, C₁-C₃ fluoroalkyl and saturated monocyclic C₃-C₅cycloalkyl;R2 is selected from the group consisting of linear or branched C₁-C₈alkyl, saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl,tetrahydrofuranyl, and tetrahydropyranyl; all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of methyl, fluorine, hydroxy, cyano andmethoxy;R3 is methyl substituted with phenyl, pyridonyl, pyridinyl, pyrimidinylor pyrazinyl all of which can be optionally substituted one or moretimes with one or more substituents selected from the group consistingof halogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxyand C₁-C₃ alkoxy; orR3 is methyl substituted with a 5-membered heteroaryl which isoptionally substituted with one or more substituents selected fromhalogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxy andC₁-C₃ alkoxy; orR3 is ethyl substituted with phenyl, pyridonyl, pyridinyl, pyrimidinylor pyrazinyl all of which can be optionally substituted one or moretimes with one or more substituents selected from the group consistingof halogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxyand C₁-C₃ alkoxy; orR3 is ethyl substituted with a 5-membered heteroaryl which is optionallysubstituted with one or more substituents selected from halogen, cyano,C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxy and C₁-C₃ alkoxy; orL is CH₂ and R3 is NH which is substituted with phenyl, pyridonyl,pyridinyl, pyrimidinyl or pyrazinyl all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of halogen, cyano, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ fluoroalkoxy and C₁-C₃ alkoxy; orL is CH₂ and R3 is NH which is substituted with a 5-membered heteroarylwhich is optionally substituted with one or more substituents selectedfrom halogen, cyano. C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxyand C₁-C₃ alkoxy;R4 is phenyl, pyridinyl or pyridonyl all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of halogen, cyano, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₄ deutereoalkyl, C₁-C₃ fluoroalkoxy, cyclopropyloxy,C₁-C₃ alkoxy. C₁-C₃ deutereoalkoxy and —N—R5R6 wherein R5 and R6 areeach independently selected from H, C₁-C₃ alkyl and C₁-C₃ deutereoalkyl;orR4 is a 5-membered heteroaryl which is optionally substituted with oneor more substituents selected from halogen, cyano, C₁-C₄ alkyl, C₁-C₄fluoroalkyl, C₁-C₄ deutereoalkyl, C₁-C₃ fluoroalkoxy, cyclopropyloxy,C₁-C₃ alkoxy, C₁-C₃ deutereoalkoxy and —N—R5R6 wherein R5 and R6 areeach independently selected from H, C₁-C₃ alkyl and C₁-C₃ deutereoalkyl;orR4 is a 4, 5 or 6 membered saturated heterocycle all of which can beoptionally substituted with one or more substituents selected from oxo,C₁-C₄ alkyl and C₁-C₄ fluoroalkyl; and pharmaceutically acceptable saltsthereof.

E2. The compound according to embodiment 1, wherein

L is selected from the group consisting of NH, CH₂, S and O;R1 is selected from the group consisting of hydrogen, linear or branchedC₁-C₅ alkyl, C₁-C₃ fluoroalkyl and saturated monocyclic C₃-C₅cycloalkyl;R2 is selected from the group consisting of linear or branched C₁-C₈alkyl, saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl,tetrahydrofuranyl, and tetrahydropyranyl; all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of methyl, fluorine, hydroxy, cyano andmethoxy;R3 is methyl substituted with phenyl, pyridonyl, pyridinyl, pyrimidinylor pyrazinyl all of which can be optionally substituted one or moretimes with one or more substituents selected from the group consistingof halogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxyand C₁-C₃ alkoxy; orR3 is methyl substituted with a 5-membered heteroaryl which isoptionally substituted with one or more substituents selected fromhalogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxy andC₁-C₃ alkoxy; orR3 is ethyl substituted with phenyl, pyridonyl, pyridinyl, pyrimidinylor pyrazinyl all of which can be optionally substituted one or moretimes with one or more substituents selected from the group consistingof halogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxyand C₁-C₃ alkoxy; orR3 is ethyl substituted with a 5-membered heteroaryl which is optionallysubstituted with one or more substituents selected from halogen, cyano,C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxy and C₁-C₃ alkoxy;R4 is phenyl, pyridinyl or pyridonyl all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of halogen, cyano, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ deutereoalkyl, C₁-C₅ fluoroalkoxy, cyclopropyloxy,C₁-C₅ alkoxy, C₁-C₃ deutereoalkoxy and —N—R5R6 wherein R5 and R6 areeach independently selected from H, C₁-C₅ alkyl and C₁-C₅ deutereoalkyl;orR4 is a 5-membered heteroaryl which is optionally substituted with oneor more substituents selected from halogen, cyano, C₁-C₃ alkyl, C₁-C₅fluoroalkyl, C₁-C₃ deutereoalkyl, C₁-C₃ fluoroalkoxy, cyclopropyloxy,C₁-C₃ alkoxy. C₁-C₃ deutereoalkoxy and —N—R5R6 wherein R5 and R6 areeach independently selected from H, C₁-C₃ alkyl and C₁-C₃ deutereoalkyl;orR4 is a 4, 5 or 6 membered saturated heterocycle all of which can beoptionally substituted with one or more substituents selected from oxo,C₁-C₄ alkyl and C₁-C₄ fluoroalkyl;E3. The compound according to any of embodiments 1 or 2, wherein L isNH.E4. The compound according to any of embodiments 1 or 2, wherein L isCH₂.E5. The compound according to any of embodiments 1 or 2, wherein L is S.E6. The compound according to any of embodiments 1 or 2, wherein L is O.E7. The compound according to embodiment 1, whereinL is CH₂ and R3 is NH which is substituted with phenyl, pyridonyl,pyridinyl, pyrimidinyl or pyrazinyl all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of halogen, cyano, C₁-C₃ alkyl, C₁-C₅fluoroalkyl, C₁-C₅ fluoroalkoxy and C₁-C₅ alkoxy; orL is CH₂ and R3 is NH which is substituted with a 5-membered heteroarylwhich is optionally substituted with one or more substituents selectedfrom halogen, cyano, C₁-C₃ alkyl, C₁-C₅ fluoroalkyl, C₁-C₅ fluoroalkoxyand C₁-C₅ alkoxy.E8. The compound according to anyone of embodiments 1-7, wherein R2 isselected from the group consisting of linear or branched C₁-C₈ alkyl,saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl, tetrahydrofuranyl andtetrahydropyranyl, all of which are unsubstituted.E9. The compound according to embodiment 8, wherein R2 is selected fromthe group consisting of linear or branched C₁-C₄ alkyl, cyclopropyl,oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.E10. The compound according to anyone of embodiments 1-9, wherein R3 ismethyl substituted with phenyl, pyridonyl, pyridinyl, pyrimidinyl orpyrazinyl all of which can be optionally substituted with one or moremethyl.E11. The compound according to embodiment 10, wherein R3 is methylsubstituted with phenyl, pyridonyl, pyridinyl, pyrimidinyl or pyrazinyl,all of which can be substituted with one methyl.E12. The compound according to embodiment 10, wherein R3 is methylsubstituted with phenyl, pyridonyl, pyridinyl, pyrimidinyl or pyrazinyl,all of which are unsubstituted.E13. The compound according to anyone of embodiments 1-9, wherein R3 isethyl substituted with phenyl, pyridonyl, pyridinyl, pyrimidinyl orpyrazinyl all of which can be optionally substituted with one or moremethyl.E14. The compound according to embodiment 13, wherein R3 is ethylsubstituted with phenyl, pyridonyl, pyridinyl, pyrimidinyl or pyrazinylall of which can be substituted with one methyl.E15. The compound according to embodiment 13, wherein R3 is ethylsubstituted with phenyl, pyridonyl, pyridinyl, pyrimidinyl or pyrazinylall of which are unsubstituted.E16. The compound according to anyone of embodiments 1-9, wherein R3 ismethyl substituted with a 5-membered heteroaryl which is optionallysubstituted with one or more methyl.E17. The compound according to anyone of embodiments 1-9, wherein R3 isethyl substituted with a 5-membered heteroaryl which is optionallysubstituted with one or more methyl.E18. The compound according to anyone of embodiments 16-17, wherein said5-membered heteroaryl is substituted with one methyl.E19. The compound according to anyone of embodiments 16-17, wherein said5-membered heteroaryl is unsubstituted.E20. The compound according to anyone of embodiments 16-19, wherein said5-membered heteroaryl is selected from thiazolyl, oxazoyl, isoxazolyl,triazolyl, pyrazolyl, tetrazolyl, imidazolyl, oxadiazolyl andthiadiazolyl and thiophenyl.E21. The compound according to anyone of embodiments 1-20, wherein R4 isphenyl, pyridinyl or pyridonyl all of which can be optionallysubstituted one time with a substituent selected from the groupconsisting of halogen, C₁-C₃ alkyl and C₁-C₃ alkoxy.E22. The compound according to any of embodiments 1-20, wherein R4 is a5-membered heteroaryl which is optionally substituted with one or moresubstituents selected from C₁-C₃ alkyl and C₁-C₃ fluoroalkyl.E23. The compound according to embodiment 22, wherein R4 is a 5-memberedheteroaryl which is optionally substituted with one or two methyl.E24. The compound according to any of embodiments 22-23, wherein said5-membered heteroaryl is selected from thiazolyl, oxazoyl, isoxazolyl,triazolyl, pyrazoyl, tetrazoyl, imidazolyl, oxadiazolyl and thiadiazolyland thiophenyl.E25. The compound according to any of embodiments 1-20, wherein R4 is a4, 5 or 6 membered saturated heterocycle all of which can be optionallysubstituted one time with a substituent selected from oxo, C₁-C₄ alkyland C₁-C₄ fluoroalkyl.E26. The compound according any of embodiments 1-3 and 8-25 of formula(Ib)

whereinR1 is selected from the group consisting of hydrogen, linear or branchedC₁-C₅ alkyl, and saturated monocyclic C₃-C₅ cycloalkyl;R2 is selected from the group consisting of linear or branched C₁-C₈alkyl, saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl,tetrahydrofuranyl and tetrahydropyranyl, all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of methyl, fluorine, hydroxy, cyano andmethoxy;R3 is methyl substituted with phenyl, pyridonyl or pyridinyl, all ofwhich can be optionally substituted one or more times with one or moresubstituents selected from the group consisting of halogen, C₁-C₃ alkyland methoxy; orR3 is methyl substituted with a 5-membered heteroaryl which isoptionally substituted with one or more substituents selected from C₁-C₃alkyl and C₁-C₃ fluoroalkyl; orR3 is ethyl substituted with phenyl, pyridonyl or pyridinyl, all ofwhich can be optionally substituted one or more times with one or moresubstituents selected from the group consisting of halogen, C₁-C₃ alkyland methoxy; orR3 is ethyl substituted with a 5-membered heteroaryl which is optionallysubstituted with one or more substituents selected from C₁-C₃ alkyl andC₁-C₃ fluoroalkyl;R4 is phenyl, pyridinyl or pyridonyl, all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of halogen, C₁-C₃ alkyl and C₁-C₃ alkoxy; orR4 is a 5-membered heteroaryl which is optionally substituted with oneor more substituents selected from C₁-C₃ alkyl and C₁-C₃ fluoroalkyl;and pharmaceutically acceptable salts thereof.E27. The compound according to embodiment 1, wherein the compound isselected from the group consisting of:

-   1:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   2:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methylthiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   3:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methylisoxazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   4:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyloxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   5:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyltriazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine:-   6:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methyltriazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   7:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   8:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   9:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   10:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(3-methylisoxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   11:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   12:    1-cyclopropyl-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   13:    5-(2-ethoxy-3-pyridyl)-N-[(1-methylpyrazol-4-yl)methyl]-1-propyl-pyrazolo[4,3-b]pyridin-7-amine;-   14:    5-(2-ethoxypyridin-3-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   15:    5-(2-ethoxypyridin-3-yl)-1-methyl-N-(1-(1-methyl-H-pyrazol-4-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   16:    5-(2-ethoxypyridin-3-yl)-1-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   17:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methylimidazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   18:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   19:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   20:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(thiazol-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   21:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methylimidazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   22:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(4-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   23:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(m-tolylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   24:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(p-tolylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   25:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   26:    5-(2-ethoxy-3-pyridyl)-1-ethyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   27:    5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine;-   28:    5-(2-ethoxy-3-pyridyl)-1,3-dimethyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   29:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methylthiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   30:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   31:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   32:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   33:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   34:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-3-thienyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   35:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methyl-2-thienyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   36:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-2-thienyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   37:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyloxazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   38:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyloxazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   39:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   40:    5-(2-ethoxy-3-pyridyl)-N-(1H-imidazol-4-ylmethyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   41:    N-benzyl-5-(2-ethoxy-3-pyridyl)-1-isopropyl-pyrazolo[4,3-b]pyridin-7-amine-   42:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methylisoxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   43:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine:-   44:    N-[(1,5-dimethylpyrazol-3-yl)methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-pyrazolo[4,3-b]pyridin-7-amine;-   45:    3-(1-isopropyl-3-methyl-7-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpyridin-2(1H)-one;-   46:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((2-methyl-1H-imidazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   47:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((5-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   48:    5-(2-ethoxypyridin-3-yl)-1-ethyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   49:    3-(1-isopropyl-3-methyl-7-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpyridin-2(1H)-one;-   50:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((4-methyloxazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   51:    N-((1,2-dimethyl-1H-imidazol-4-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   52:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   53:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1,2,4-oxadiazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   54:    N-[(1,5-dimethylpyrazol-3-yl)methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   55:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1H-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine:-   56:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   57:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   58:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((1-methyl-1H-imidazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine    2,2,2-trifluoroacetate;-   59:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1,3,4-oxadiazol-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   60:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   61:    5-(1,3-dimethylpyrazol-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine:-   62:    1-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   63:    1-isopropyl-5-(2-methoxyphenyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   64:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-phenyl-pyrazolo[4,3-b]pyridin-7-amine;-   65:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(2-methyl-3-thienyl)pyrazolo[4,3-b]pyridin-7-amine;-   66:    5-(1,5-dimethylpyrazol-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   67:    5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2:-   68:    3-methyl-1-[1-methylpropyl]-N-[(2-methyltetrazol-5-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   69:    5-(2-ethoxy-3-pyridyl)-1-[1-methylpropy]-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 1;-   70:    5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   71:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   72:    5-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]oxymethyl]-2-methyl-oxazole;-   73:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrimidin-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   74:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrimidin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   75:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methylpyrimidin-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   76:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrazin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   77:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine;-   78:    4-[[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]amino]methyl]-1-methyl-pyridin-2-one;-   79:    5-(2-(ethylamino)pyridin-3-yl)-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   81:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   82:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxypyrazin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   83:    5-(2-ethoxy-3-pyridyl)-N-[(5-fluoropyrimidin-2-yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   84:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   85:    5-(2-ethoxy-3-pyridyl)-N-[(2-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   86:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   87:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(6-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   88:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2-methoxyphenyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   89:    5-(2-ethoxy-3-pyridyl)-N-[(2-fluorophenyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   90:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[2-(trifluoromethyl)phenyl]methyl]pyrazolo[4,3-b]pyridin-7-amine;-   91:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methoxypyrazin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   92:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine:-   93:    1-isopropyl-3-methyl-N-[(2-methyltetrazol-5-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;-   94:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;-   95:    1-isopropyl-5-(2-methoxy-3-pyridyl)-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   96:    1-isopropyl-5-(2-methoxy-3-pyridyl)-N-[(6-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   97:    5-(2-isopropoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   98:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   99:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(2H-tetrazol-5-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   100:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   101:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(6-methyl-2-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   102:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   103:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-4-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   104:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-[(2-methoxy-4-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   105:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   106:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   107:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[6-(trifluoromethyl-2-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine;-   108:    3-[[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]amino]methyl]-1-methyl-pyridin-2-one;-   109:    5-(2-ethoxy-3-pyridyl)-N-[(1-ethylpyrazol-4-yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   110:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-propylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   111:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   112:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-[(5-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   113:    5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methylthiazol-4-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine;-   114:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxypyrazin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   115:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(3-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   116:    5-(2-ethoxy-3-pyridyl)-N-[(6-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine:-   117:    N-[[6-(difluoromethyl)-3-pyridyl]methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   118:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   119:    5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 1;-   120:    5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   121:    5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 1;-   122:    5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2:-   123:    5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 1;-   124:    5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   125:    5-(2-ethoxy-3-pyridyl)-N-[(5-methoxy-3-pyridyl)methyl]-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   126:    5-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   127:    5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropy]-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2:-   128:    5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   129:    5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methyloxazol-4-yl)methyl]-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   130:    5-(2-ethoxy-3-pyridyl)-N-(1H-imidazol-4-ylmethyl)-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   131:    5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropy]-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   132:    5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methylimidazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   133:    5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methyloxazol-5-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   134:    3-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   135:    3-methyl-1-[1-methylpropyl]-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   136:    5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 1;-   137:    5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   138:    5-(2-ethoxy-3-pyridyl)-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 1;-   139:    5-(2-ethoxy-3-pyridyl)-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   140:    5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 1:-   141:    5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   142:    1-isopropyl-3-methyl-N-[(1-methylimidazol-4-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;-   143:    1-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   144:    5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,    enantiomer 2;-   145:    1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;-   146:    1-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)-N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   147:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-thiazol-2-yl-pyrazolo[4,3-b]pyridin-7-amine;-   148:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(5-methylthiazol-2-yl)pyrazolo[4,3-b]pyridin-7-amine;-   149:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(4-methylthiazol-2-yl)pyrazolo[4,3-b]pyridin-7-amine;-   150:    3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-5-methyl-oxazolidin-2-one;-   151:    3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]oxazolidin-2-one;-   152:    1-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]azetidin-2-one;-   153:    1-tert-butyl-3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]imidazolidin-2-one;-   154:    1-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]pyrrolidin-2-one;-   155:    3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-4-methyl-oxazolidin-2-one;-   156:    4-ethyl-3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]oxazolidin-2-one;-   157:    N-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]methyl]-5-methoxy-pyridin-3-amine;-   158:    N-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]methyl]-1-methyl-1,2,4-triazol-3-amine;-   159:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-7-[2-(5-methoxy-3-pyridyl)ethyl]-3-methyl-pyrazolo[4,3-b]pyridine;-   160:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-7-[2-(1-methyl-1,2,4-triazol-3-yl)ethyl]pyrazolo[4,3-b]pyridine;-   161:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   162:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   163:    5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine;-   164:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylsulfanyl]pyrazolo[4,3-b]pyridine;-   165:    N-[[1-(difluoromethyl)pyrazol-4-yl]methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   166:    5-(2-ethoxy-3-pyridyl)-N-[[5-(fluoromethyl)isoxazol-3-yl]methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   167:    5-(2-ethoxy-3-pyridyl)-N-[[3-(fluoromethyl)isoxazol-5-yl]methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   168:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-oxazol-2-yl-pyrazolo[4,3-b]pyridin-7-amine;-   169:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(3-methyltriazol-4-yl)pyrazolo[4,3-b]pyridin-7-amine;-   170:    1-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine;-   171:    3-[1-isopropyl-7-[(2-methoxy-3-pyridyl)methylamino]-3-methyl-pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one;-   172:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methoxy-4-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   173:    1-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   174:    5-(2-cyclopropoxypyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   175:    1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   176:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxypyrimidin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   177:    3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one;-   178:    N-[[2-(difluoromethyl)-3-pyridyl]methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   179:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxypyrimidin-4-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   180:    5-(2-(ethoxy-1,1-d₂)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   181:    5-(2-(ethoxy-d₅)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   182:    5-(2-(ethoxy-2,2,2-d₃)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   183:    1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-5-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   184:    3-(difluoromethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   185:    1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(1H-1,2,4-triazol-1-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   186:    3-[1-isopropyl-3-methyl-7-[(1-methyl-1,2,4-triazol-3-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one;-   187:    3-[1-isopropyl-3-methyl-7-(1H-pyrazol-3-ylmethylamino)pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one;-   188:    5-[2-(difluoromethoxy)-3-pyridyl]-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   189:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxypyrimidin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   190:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxypyrimidin-5-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   191:    5-(2-ethoxy-3-pyridyl)-N-[(2-ethoxy-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   192:    5-[2-(dimethylamino)-3-pyridyl]-1-isopropyl-N-[(4-methoxyphenyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   193:    3-[1-isopropyl-3-methyl-7-[[2-(trifluoromethyl)-3-pyridyl]methylamino]pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one;-   194:    1-isopropyl-3-methyl-5-(3-methylisoxazol-4-yl)-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   195:    1-isopropyl-3-methyl-5-(1-methyl-1H-1,2,4-triazol-5-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   196:    1-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   197:    5-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine;-   198:    5-(2-(ethyl(methyl)amino)pyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   199:    5-(2-ethoxypyridin-3-yl)-3-(fluoromethyl)-1-isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   200:    1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(4-methyloxazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   201:    5-[2-(dimethylamino)-3-pyridyl]-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   202:    1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(4-methyloxazol-2-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   203:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(4-methyl-1,2,4-triazol-3-yl)pyrazolo[4,3-b]pyridin-7-amine;    and pharmaceutically acceptable salts of any of these compounds.    E28. The compound according to embodiment 1, wherein the compound is    selected from the group consisting of:-   1:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   2:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methylthiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   3:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methylisoxazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   4:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyloxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   5:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyltriazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   6:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methyltriazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   7:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   8:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   9:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   10:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(3-methylisoxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   11:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   12:    1-cyclopropyl-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   13:    5-(2-ethoxy-3-pyridyl)-N-[(1-methylpyrazol-4-yl)methyl]-1-propyl-pyrazolo[4,3-b]pyridin-7-amine;-   14:    5-(2-ethoxypyridin-3-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   15:    5-(2-ethoxypyridin-3-yl)-1-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-7-amine    (racemic);-   15a:    (R)-5-(2-ethoxypyridin-3-yl)-1-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   15b:    (S)-5-(2-ethoxypyridin-3-yl)-1-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-7-amine:-   16:    5-(2-ethoxypyridin-3-yl)-1-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   17:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methylimidazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   18:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   19:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   20:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(thiazol-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   21:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methylimidazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   22:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(4-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   23:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(m-tolylmethyl)pyrazolo[4,3-b]pyridin-7-amine:-   24:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(p-tolylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   25:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   26:    5-(2-ethoxy-3-pyridyl)-1-ethyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine:-   27:    5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine;-   28:    5-(2-ethoxy-3-pyridyl)-1,3-dimethyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   29:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methylthiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   30:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   31:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   32:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine:-   33:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   34:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-3-thienyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   35:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methyl-2-thienyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   36:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-2-thienyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   37:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyloxazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   38:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyloxazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   39:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   40:    5-(2-ethoxy-3-pyridyl)-N-(1H-imidazol-4-ylmethyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   41:    N-benzyl-5-(2-ethoxy-3-pyridyl)-1-isopropyl-pyrazolo[4,3-b]pyridin-7-amine;-   42:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methylisoxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   43:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine:-   44:    N-[(1,5-dimethylpyrazol-3-yl)methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-pyrazolo[4,3-b]pyridin-7-amine;-   45:    3-(1-isopropyl-3-methyl-7-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-1-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpyridin-2(1H)-one;-   46:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((2-methyl-1H-imidazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   47:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((5-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   48:    5-(2-ethoxypyridin-3-yl)-1-ethyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   49:    3-(1-isopropyl-3-methyl-7-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpyridin-2(1H)-one;-   50:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((4-methyloxazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine:-   51:    N-((1,2-dimethyl-1H-imidazol-4-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   52:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine:-   53:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1,2,4-oxadiazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine:-   54:    N-[(1,5-dimethylpyrazol-3-yl)methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   55:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1H-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   56:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   57:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   58:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((1-methyl-1H-imidazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine    2,2,2-trifluoroacetate;-   59:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1,3,4-oxadiazol-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   60:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   61:    5-(1,3-dimethylpyrazol-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   62:    1-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   63:    1-isopropyl-5-(2-methoxyphenyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   64:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-phenyl-pyrazolo[4,3-b]pyridin-7-amine;-   65:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(2-methyl-3-thienyl)pyrazolo[4,3-b]pyridin-7-amine;-   66:    5-(1,5-dimethylpyrazol-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   67a:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   67b:    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   68a:    (R)-3-methyl-1-[1-methylpropyl]-N-[(2-methyltetrazol-5-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;-   68b:    (S)-3-methyl-1-[1-methylpropyl]-N-[(2-methyltetrazol-5-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;-   69:    (R)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   70:    (R)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   71:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   72:    5-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]oxymethyl]-2-methyl-oxazole;-   73:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrimidin-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   74:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrimidin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   75:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methylpyrimidin-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   76:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrazin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   77:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine;-   78:    4-[[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]amino]methyl]-1-methyl-pyridin-2-one;-   79:    5-(2-(ethylamino)pyridin-3-yl)-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   81:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   82:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxypyrazin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   83:    5-(2-ethoxy-3-pyridyl)-N-[(5-fluoropyrimidin-2-yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   84:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   85:    5-(2-ethoxy-3-pyridyl)-N-[(2-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   86:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine:-   87:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(6-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   88:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2-methoxyphenyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   89:    5-(2-ethoxy-3-pyridyl)-N-[(2-fluorophenyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   90:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[2-(trifluoromethyl)phenyl]methyl]pyrazolo[4,3-b]pyridin-7-amine;-   91:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methoxypyrazin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   92:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-[(4-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   93:    1-isopropyl-3-methyl-N-[(2-methyltetrazol-5-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;-   94:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;-   95:    1-isopropyl-5-(2-methoxy-3-pyridyl)-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   96:    1-isopropyl-5-(2-methoxy-3-pyridyl)-N-[(6-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   97:    5-(2-isopropoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   98:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   99:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(2H-tetrazol-5-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   100:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   101:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(6-methyl-2-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   102:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   103:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-4-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   104:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2-methoxy-4-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine:-   105:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   106:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   107:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[6-(trifluoromethyl)-2-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine;-   108:    3-[[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]amino]methyl]-1-methyl-pyridin-2-one;-   109:    5-(2-ethoxy-3-pyridyl)-N-[(1-ethylpyrazol-4-yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   110:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-propylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   111:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   112:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   113:    5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methylthiazol-4-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine;-   114:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxypyrazin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   115:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(3-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   116:    5-(2-ethoxy-3-pyridyl)-N-[(6-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   117:    N-[[6-(difluoromethyl)-3-pyridyl]methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   118:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   119:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   120:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   121:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   122:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   123:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;-   124:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;-   125a:    (R)-5-(2-ethoxy-3-pyridyl)-N-[(5-methoxy-3-pyridyl)methyl]-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;-   125b:    (S)-5-(2-ethoxy-3-pyridyl)-N-[(5-methoxy-3-pyridyl)methyl]-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;-   126a:    (R)-5-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-3-methyl-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine;-   126b:    (S)-5-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-3-methyl-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine;-   127a:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   127b:    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   128a:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;-   128b:    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine;-   129a:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methyloxazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;-   129b:    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methyloxazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;-   130a:    (R)-5-(2-ethoxy-3-pyridyl)-N-(1H-imidazol-4-ylmethyl)-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;-   130b:    (S)-5-(2-ethoxy-3-pyridyl)-N-(1H-imidazol-4-ylmethyl)-3-methyl-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine;-   131a:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   131b:    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   132a:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methylimidazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;-   132b:    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methylimidazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;-   133a:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methyloxazol-5-yl)methyl]-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine;-   133b:    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methyloxazol-5-yl)methyl]-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine;-   134a:    (R)-3-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;-   134b:    (S)-3-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;-   135a:    (R)-3-methyl-1-[1-methylpropy]-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   135b:    (S)-3-methyl-1-[1-methylpropyl]-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   136:    (R)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropy]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   137:    (R)-5-(2-ethoxy-3-pyridyl)-1-[I-methylpropy]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   138:    (R)-5-(2-ethoxy-3-pyridyl)-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;-   139:    (R)-5-(2-ethoxy-3-pyridyl)-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;-   140:    (R)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropy]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropy]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   141:    (R)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropy]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   142:    1-isopropyl-3-methyl-N-[(1-methylimidazol-4-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;-   143:    1-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   144a:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[-methylpropyl]-N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   144b:    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   145:    1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;-   146:    1-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)-N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   147:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-thiazol-2-yl-pyrazolo[4,3-b]pyridin-7-amine;-   148:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(5-methylthiazol-2-yl)pyrazolo[4,3-b]pyridin-7-amine;-   149:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(4-methylthiazol-2-yl)pyrazolo[4,3-b]pyridin-7-amine;-   150:    3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-5-methyl-oxazolidin-2-one;-   151:    3-[l-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]oxazolidin-2-one;-   152:    1-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]azetidin-2-one;-   153:    1-tert-butyl-3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]imidazolidin-2-one:-   154:    1-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]pyrrolidin-2-one;-   155:    3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-4-methyl-oxazolidin-2-one;-   156:    4-ethyl-3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]oxazolidin-2-one;-   157:    N-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]methyl]-5-methoxy-pyridin-3-amine;-   158:    N-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]methyl]-1-methyl-1,2,4-triazol-3-amine;-   159:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-7-[2-(5-methoxy-3-pyridyl)ethyl]-3-methyl-pyrazolo[4,3-b]pyridine;-   160:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-7-[2-(1-methyl-1,2,4-triazol-3-yl)ethyl]pyrazolo[4,3-b]pyridine;-   161:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   162:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   163:    5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine;-   164:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylsulfanyl]pyrazolo[4,3-b]pyridine;-   165:    N-[[1-(difluoromethyl)pyrazol-4-yl]methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   166:    5-(2-ethoxy-3-pyridyl)-N-[[5-(fluoromethyl)isoxazol-3-yl]methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   167:    5-(2-ethoxy-3-pyridyl)-N-[[3-(fluoromethyl)isoxazol-5-yl]methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   168:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-oxazol-2-yl-pyrazolo[4,3-b]pyridin-7-amine;-   169:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(3-methyltriazol-4-yl)pyrazolo[4,3-b]pyridin-7-amine;-   170:    1-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine;-   171:    3-[1-isopropyl-7-[(2-methoxy-3-pyridyl)methylamino]-3-methyl-pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one;-   172:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methoxy-4-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   173:    1-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   174:    5-(2-cyclopropoxypyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   175:    1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   176:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxypyrimidin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   177:    3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one;-   178:    N-[[2-(difluoromethyl)-3-pyridyl]methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   179:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxypyrimidin-4-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   180:    5-(2-(ethoxy-1,1-d₂)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   181:    5-(2-(ethoxy-d₅)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   182:    5-(2-(ethoxy-2,2,2-d₃)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   183:    1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-5-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   184:    3-(difluoromethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   185:    1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(1H-1,2,4-triazol-1-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   186:    3-[1-isopropyl-3-methyl-7-[(1-methyl-1,2,4-triazol-3-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one;-   187:    3-[1-isopropyl-3-methyl-7-(1H-pyrazol-3-ylmethylamino)pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one;-   188:    5-[2-(difluoromethoxy)-3-pyridyl]-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   189:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxypyrimidin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   190:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxypyrimidin-5-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   191:    5-(2-ethoxy-3-pyridyl)-N-[(2-ethoxy-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   192:    5-[2-(dimethylamino)-3-pyridyl]-1-isopropyl-N-[(4-methoxyphenyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   193:    3-[1-isopropyl-3-methyl-7-[[2-(trifluoromethyl)-3-pyridyl]methylamino]pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one;-   194:    1-isopropyl-3-methyl-5-(3-methylisoxazol-4-yl)-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   195:    1-isopropyl-3-methyl-5-(1-methyl-1H-1,2,4-triazol-5-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   196:    1-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   197:    5-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine;-   198:    5-(2-(ethyl(methyl)amino)pyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   199:    5-(2-ethoxypyridin-3-yl)-3-(fluoromethyl)-1-isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   200:    1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(4-methyloxazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   201:    5-[2-(dimethylamino)-3-pyridyl]-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   202:    1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(4-methyloxazol-2-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   203:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(4-methyl-1,2,4-triazol-3-yl)pyrazolo[4,3-b]pyridin-7-amine;    and pharmaceutically acceptable salts of any of these compounds.    E29. The compound according to embodiment 1, wherein the compound is    selected from the group consisting of:-   6:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methyltriazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   7:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   21:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methylimidazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   29:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methylthiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine:-   32:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   39:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   47:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((5-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   50:    5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((4-methyloxazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine;-   56:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   57:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   67a:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   67b:    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   77:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine;-   82:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxypyrazin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   85:    5-(2-ethoxy-3-pyridyl)-N-[(2-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   86:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine:-   88:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2-methoxyphenyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   89:    5-(2-ethoxy-3-pyridyl)-N-[(2-fluorophenyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   90:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[2-(trifluoromethyl)phenyl]methyl]pyrazolo[4,3-b]pyridin-7-amine;-   92:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   94:    1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;-   100:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   101:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(6-methyl-2-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   107:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[6-(trifluoromethyl)-2-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine;-   111:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   113:    5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methylthiazol-4-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine;-   118:    5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;-   119:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropy]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   120:    (R)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropy]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   135a:    (R)-3-methyl-1-[1-methylpropy]-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   135b:    (S)-3-methyl-1-[1-methylpropyl]-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   136:    (R)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropy]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   137:    (R)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   137:    (R)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;-   140:    (R)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   141:    (R)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine    or    (S)-5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;-   180:    5-(2-(ethoxy-1,1-d₂)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   181:    5-(2-(ethoxy-d₅)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   182:    5-(2-(ethoxy-2,2,2-d₃)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   191:    5-(2-ethoxy-3-pyridyl)-N-[(2-ethoxy-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;    and pharmaceutically acceptable salts of any of these compounds.    E30. A compound of any one of embodiments 1-29, wherein said    compound has a PDE1A, PDE1B or PDE1C IC₅₀ value, determined as    described in the section “PDE1 inhibition assay”, of 10 micro molar    or less, such as 5 micro molar or less, such as 4 micro molar or    less, such as 3 micro molar or less, such as 2 micro molar or less,    such as 1 micro molar or less, such as 500 nM or less, such as 400    nM or less, such as 300 nM or less, such as 200 nM or less, such as    100 nM or less.    E31. A compound of any one of embodiments 1-29 for use in therapy.    E32. A compound according to any of embodiments 1-29, for use as a    medicament.    E33. A pharmaceutical composition comprising a therapeutically    effective amount of a compound of any one of embodiments 1-29 and    one or more pharmaceutically acceptable carriers, diluents and    excipients.    E34. A compound according to any of embodiments 1-29 for use in the    treatment of a neurodegenerative disorder, selected from the group    consisting of Alzheimer's Disease, Parkinson's Disease and    Huntington's Disease or for the treatment of a psychiatric disorder    such as Attention Deficit hyperactivity Disorder (ADHD), depression,    anxiety, narcolepsy, cognitive impairment and cognitive impairment    associated with schizophrenia (CIAS), or another brain disease like    restless leg syndrome.    E35. A method for the treatment of a neurodegenerative disorder,    selected from the group consisting of Alzheimer's Disease,    Parkinson's Disease and Huntington's Disease or for the treatment of    a psychiatric disorder such as Attention Deficit hyperactivity    Disorder (ADHD), depression, anxiety, narcolepsy, cognitive    impairment and cognitive impairment associated with schizophrenia    (CIAS), or another brain disease like restless leg syndrome, which    method comprises the administration of a therapeutically effective    amount of a compound according to any of embodiments 1-29 to a    patient in need thereof.    E36. Use of a compound according to any of embodiments 1-29, for the    manufacture of a medicament for the treatment of a neurodegenerative    disorder, selected from the group consisting of Alzheimer's Disease,    Parkinson's Disease and Huntington's Disease or for the treatment of    a psychiatric disorder such as Attention Deficit hyperactivity    Disorder (ADHD), depression, anxiety, narcolepsy, cognitive    impairment and cognitive impairment associated with schizophrenia    (CIAS), or another brain disease like restless leg syndrome.

All references, including publications, patent applications and patents,cited herein are hereby incorporated by reference in their entirety andto the same extent as if each reference were individually andspecifically indicated to be incorporated by reference and were setforth in its entirety (to the maximum extent permitted by law).

Headings and sub-headings are used herein for convenience only, andshould not be construed as limiting the invention in any way.

The use of any and all examples, or exemplary language (including “forinstance”, “for example”, “e.g.”, and “as such”) in the presentspecification is intended merely to better illuminate the invention, anddoes not pose a limitation on the scope of invention unless otherwiseindicated.

The citation and incorporation of patent documents herein is done forconvenience only, and does not reflect any view of the validity,patentability and/or enforceability of such patent documents.

The present invention includes all modifications and equivalents of thesubject-matter recited in the claims appended hereto, as permitted byapplicable law.

Compounds of the Invention

TABLE 1 Compounds of the invention PDE1A, PDE1B, PDE1C, IC₅₀ IC₅₀ IC₅₀Example Compound (nM) (nM) (nM) 15-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 18 1.6 40[(5-methyl-1,3,4-oxadiazol-2- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine 25-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 0.46 0.071 4.9[(5-methylthiazol-2-y)methyl]pyrazolo[4,3- b]pyridin-7-amine 35-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 0.8 0.11 3[(5-methylisoxazol-3-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 45-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 8.6 0.86 19[(2-methyloxazol-5-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 55-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 11 1.8 28[(2-methyltriazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 65-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 4.8 0.22 5.6[(1-methyltriazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 75-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 21 1.1 37(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridin- 7-amine 85-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 2.9 0.34 8.9[(2-methyltetrazol-5-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 95-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl- 2.6 0.49 17N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H- pyrazolo[4,3-b]pyridin-7-amine10 5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 4.1 0.47 14[(3-methylisoxazol-5-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 115-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 9.6 0.72 30[(2-methylthiazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 121-cyclopropyl-5-(2-ethoxy-3-pyridyl)-3-methyl- 200 60 690N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 135-(2-ethoxy-3-pyridyl)-N-[(1-methylpyrazol-4- 90 15 340yl)methyl]-1-propyl-pyrazolo[4,3-b]pyridin-7- amine 145-(2-ethoxypyridin-3-yl)-N-((1-methyl-1H- 450 38 300pyrazol-4-yl)methyl)-1-(oxetan-3-yl)-1H- pyrazolo[4,3-b]pyridin-7-amine15 5-(2-ethoxypyridin-3-yl)-1-methyl-N-(1-(1- 820 200 36%methyl-1H-pyrazol-4-yl)ethyl)-1H- inhibitionpyrazolo[4,3-b]pyridin-7-amine (racemic) at 10 μM 165-(2-ethoxypyridin-3-yl)-1-methyl-N-((1- 670 92 1800methyl-1H-pyrazol-4-yl)methyl)-1H- pyrazolo[4,3-b]pyridin-7-amine 175-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1- 700 54 970methylimidazol-2-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 185-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1- 450 73 640methyl-1H-pyrazol-5-yl)methyl)-1H- pyrazolo[4,3-b]pyridin-7-amine 195-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1- 66 4.6 150methyl-1H-pyrazol-3-yl)methyl)-1H- pyrazolo[4,3-b]pyridin-7-amine 205-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(thiazol- 520 37 6002-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine 215-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1- 8.9 0.44 29methylimidazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 225-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(4- 250 50 430pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine 235-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(m- 240 38 750tolylmethyl)pyrazolo[4,3-b]pyridin-7-amine 245-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(p- 380 160 1200tolylmethyl)pyrazolo[4,3-b]pyridin-7-amine 255-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1- 56 4.6 150methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 265-(2-ethoxy-3-pyridyl)-1-ethyl-N-[(1- 140 22 440methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 275-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1- 94 6.6 170methylpyrazol-4-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine 285-(2-ethoxy-3-pyridyl)-1,3-dimethyl-N-[(1- 550 85 1900methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 295-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 27 1.1 44[(4-methylthiazol-2-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 305-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 15 1.3 31[(3-methyl-1,2,4-oxadiazol-5- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine31 5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 1.2 0.11 2.1[(1-methyl-1,2,4-triazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine 325-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 4.6 0.14 6.2[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 335-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 1.6 0.41 7.9[(5-methyl-1,3,4-thiadiazol-2- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine34 5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 8.1 1.8 21[(5-methyl-3-thienyl)methyl]pyrazolo[4,3- b]pyridin-7-amine 355-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 7.3 1.7 32[(4-methyl-2-thienyl)methyl]pyrazolo[4,3- b]pyridin-7-amine 365-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 24 5.2 41[(5-methyl-2-thienyl)methyl]pyrazolo[4,3- b]pyridin-7-amine 375-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 5.9 0.43 18[(2-methyloxazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 385-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 1.1 0.24 13[(5-methyloxazol-2-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 395-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 8.1 0.43 13(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin- 7-amine 405-(2-ethoxy-3-pyridyl)-N-(1H-imidazol-4- 14 1 32ylmethyl)-1-isopropyl-3-methyl-pyrazolo[4,3- b]pyridin-7-amine 41N-benzyl-5-(2-ethoxy-3-pyridyl)-1-isopropyl- 500 45 500pyrazolo[4,3-b]pyridin-7-amine 425-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3- 82 5.8 180methylisoxazol-5-yljmethyl)pyrazolo[4,3- b]pyridin-7-amine 435-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5- 30 2.4 80methyl-1,2,4-oxadiazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine 44N-[(1,5-dimethylpyrazol-3-yl)methyl]-5-(2- 19 1.4 70ethoxy-3-pyridyl)-1-isopropyl-pyrazolo[4,3- b]pyridin-7-amine 453-(1-isopropyl-3-methyl-7-(((1-methyl-1H- 8 0.62 16pyrazol-4-yl)methyl)amino)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpyridin-2(1H)-one 465-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl- 5 0.42 9.7N-((2-methyl-1H-imidazol-4-yl)methyl)-1H- pyrazolo[4,3-b]pyridin-7-amine47 5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl- 1.6 0.069 1.8N-((5-methyl-1H-pyrazol-3-yl)methyl)-1H- pyrazolo[4,3-b]pyridin-7-amine48 5-(2-ethoxypyridin-3-yl)-1-ethyl-3-methyl-N- 38 6.3 170((1-methyl-1H-pyrazol-4-yl)methyl)-1H- pyrazolo[4,3-b]pyridin-7-amine 493-(1-isopropyl-3-methyl-7-(((1-methyl-1H- 170 20 420pyrazol-4-yl)methyl)amino)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpyridin-2(1H)-one 505-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl- 9 0.5 16N-((4-methyloxazol-2-yl)methyl)-1H- pyrazolo[4,3-b]pyridin-7-amine2,2,2- trifluoroacetate 51 N-((1,2-dimethyl-1H-imidazol-4-yl)methyl)-5-53 9.1 88 (2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine 2,2,2- trifluoroacetate 525-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 1.9 0.17 4.4[(5-methyl-1,2,4-oxadiazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine53 5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 9.3 0.89 17(1,2,4-oxadiazol-3-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine 54N-[(1,5-dimethylpyrazol-3-yl)methyl]-5-(2- 0.39 0.18 4.6ethoxy-3-pyridyl)-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amine55 5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 3.4 0.51 5.5[(5-methyl-1H-1,2,4-triazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine56 5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1- 16 1 45methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 575-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(1H- 98 4.8 170pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7- amine 585-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl- 1.1 0.17 2.1N-((1-methyl-1H-imidazol-4-yl)methyl)-1H- pyrazolo[4,3-b]pyridin-7-amine2,2,2- trifluoroacetate 595-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 55 12 120(1,3,4-exadiazol-2-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine 605-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 6.5 0.59 12[(1-methylpyrazol-3-yl)methyl)pyrazolo[4,3- b]pyridin-7-amine 615-(1,3-dimethylpyrazol-4-yl)-1-isopropyl-3- 550 120 680methyl-N-[(1-methylpyrazol-4- yl)methyl]pyrazole4,3-b]pyridin-7-amine 621-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl- 16 2.4 21N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 631-isopropyl-5-(2-methoxyphenyl)-3-methyl-N- 64 9.4 20[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 641-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 52 12 47yl)methyl]-5-phenyl-pyrazolo[4,3-b]pyridin-7- amine 651-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 7.9 1.2 16yl)methyl]-5-(2-methyl-3-thienyl)pyrazolo[4,3- b]pyridin-7-amine 665-(1,5-dimethylpyrazol-4-yl)-1-isopropyl-3- 210 59 220methyl-N-[(1-methylpyrazol-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine67 5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 9.6 0.64 27methylpropyl]-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 683-methyl-1-[1-methylpropyl]-N-[(2- 0.79 0.14 1.3methyltetrazol-5-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 695-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N- 14 1.2 40[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine,enantiomer 1 70 5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N- 140 14 360[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine,enantiomer 2 71 5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4- 170 18 180methylthiazol-5-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 725-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3- 14 2.4 39methyl-pyrazolo[4,3-b]pyridin-7-yl]oxymethyl]- 2-methyl-oxazole 735-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 81 9.2 140(pyrimidin-4-ylmethyl)pyrazolo[4,3-b]pyridin-7- amine 745-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 2.1 0.34 8.1(pyrimidin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7- amine 755-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 9.9 0.81 33[(4-methylpyrimidin-2-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 765-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 23 2.9 32(pyrazin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7- amine 775-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 21 0.22 64[[2-(trifluoromethyl)-3- pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine78 4-[[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3- 27 3.2 44methyl-pyrazolo[4,3-b]pyridin-7- yl]amino]methyl]-1-methyl-pyridin-2-one79 5-(2-(ethylamino)pyridin-3-yl)-1-isopropyl-3- 230 31 260methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine 815-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4- 1 0.26 4.7methoxy-2-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 825-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6- 16 1 35methoxypyrazin-2-yl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 835-(2-ethoxy-3-pyridyl)-N-[(5-fluoropyrimidin-2- 17 1.2 38yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3- b]pyridin-7-amine 845-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 19 1.8 23[(2-methyl-3-pyridyl)methyl]pyrazolo[4,3- b]pyridin-7-amine 855-(2-ethoxy-3-pyridyl)-N-[(2-fluoro-3- 8.4 0.22 27pyridyl)methyl]-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 865-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2- 20 0.36 68methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 875-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 6.3 0.95 13[(6-methyl-3-pyridyl)methyl]pyrazolo[4,3- b]pyridin-7-amine 885-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2- 110 5.1 170methoxyphenyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 895-(2-ethoxy-3-pyridyl)-N-[(2- 61 1.5 93fluorophenyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine 905-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 270 12 640 [[2-(trifluoromethyl)phenyl]methyl]pyrazolo[4,3- b]pyridin-7-amine 915-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3- 27 2.3 70methoxypyrazin-2-yl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 925-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4- 47 2.7 110methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 931-isopropyl-3-methyl-N-[(2-methyltetrazol-5- 4.3 0.96 17yl)methyl]-5-(2-propoxy-3- pyridyl)pyrazolo[4,3-b]pyridin-7-amine 941-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 1.4 0.065 4.9yl)methyl]-5-(2-propoxy-3- pyridyl)pyrazolo[4,3-b]pyridin-7-amine 951-isopropyl-5-(2-methoxy-3-pyridyl)-N-[(2- 42 6.4 28methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 961-isopropyl-5-(2-methoxy-3-pyridyl)-N-[(6- 18 3.8 5.3methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 975-(2-isopropoxy-3-pyridyl)-1-isopropyl-3- 1.4 0.6 9.1methyl-N-[(1-methylpyrazol-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine98 5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 7.2 0.58 21(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine 995-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 0.73 0.31 3.8(2H-tetrazol-5-ylmethyl)pyrazolo[4,3-b]pyridin- 7-amine 1005-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 6.3 0.39 21(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7- amine 1015-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 20 0.9 43[(6-methyl-2-pyridyl)methyl]pyrazolo[4,3- b]pyridin-7-amine 1025-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6- 8 0.73 34methoxy-2-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 1035-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 5.4 2.9 17[(2-methyl-4-pyridyl)methyl]pyrazolo[4,3- b]pyridin-7-amine 1045-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2- 2.2 0.16 6.3methoxy-4-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 1055-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 54 12 150[(2-methylpyrimidin-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 1065-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5- 2.1 0.45 3.9methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 1075-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 110 5.6 170[[6-(trifluoromethyl)-2- pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine108 3-[[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3- 2.8 0.36 12methyl-pyrazolo[4,3-b]pyridin-7- yl]amino]methyl]-1-methyl-pyridin-2-one109 5-(2-ethoxy-3-pyridyl)-N-[(1-ethylpyrazol-4- 4.9 0.66 11yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3- b]pyridin-7-amine 1105-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 11 1.1 8.5[(1-propylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 1115-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6- 28 1.4 68methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 1125-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5- 61 12 100methoxy-2-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 1135-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2- 110 5.7 130methylthiazol-4-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine 1145-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5- 24 3 46methoxypyrazin-2-yl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 1155-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 15 2 31(3-pyridylmethyl)pyrazolo[4,3-b]pyridin-7- amine 1165-(2-ethoxy-3-pyridyl)-N-[(6-fluoro-3- 21 2.4 46pyridyl)methyl]-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 117N-[[6-(difluoromethyl)-3-pyridyl]methyl]-5-(2- 18 2.3 26ethoxy-3-pyridyl)-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amine118 5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3- 13 0.42 88methoxy-2-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 1195-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 12 0.56 29methylpropyl]-N-(1H-pyrazol-3- ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 120 5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 4.6 0.27 7.6methylpropyl]-N-(1H-pyrazol-3- ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 121 5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 4 0.47 10methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 1 1225-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 2.2 0.15 3.5methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 1235-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl- 54 7 1301,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 1 1245-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl- 9.7 1.1 211,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 1255-(2-ethoxy-3-pyridyl)-N-[(5-methoxy-3- 1 0.32 4.3pyridyl)methyl]-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 1265-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4- 5.4 0.51 8.4pyridyl)methyl]-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 1275-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 1.8 0.31 5.1methylpropyl]-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 1285-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl- 1.2 0.26 4.11,2,4-oxadiazol-3-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 1295-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2- 11 1.2 25methyloxazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 1305-(2-ethoxy-3-pyridyl)-N-(1H-imidazol-4- 11 0.86 25ylmethyl)-3-methyl-1-[1- methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 131 5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 0.35 0.042 0.46methylpropyl]-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 1325-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1- 0.14 0.045 0.52methylimidazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 1335-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2- 11 1.3 23methyloxazol-5-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 1343-methyl-1-[1-methylpropyl]-N-[(1-methyl- 0.96 0.12 1.51,2,4-triazol-3-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 1353-methyl-1-[1-methylpropyl]-5-(2-propoxy-3- 1.9 0.095 3.6pyridyl)-N-(1H-pyrazol-3- ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 136 5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N- 62 3.2 100(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin- 7-amine, enantiomer 1 1375-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N- 180 12 340(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin- 7-amine, enantiomer 2 1385-(2-ethoxy-3-pyridyl)-N-[(5-methyl-1,3,4- 93 6.8 180oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 1 1395-(2-ethoxy-3-pyridyl)-N-[(5-methyl-1,3,4- 330 35 530oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 1405-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N- 32 1.7 52[(1-methyl-1,2,4-thazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 141 5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N- 44 2.2 76[(1-methyl-1,2,4-thazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 142 1-isopropyl-3-methyl-N-[(1-methylimidazol-4- 0.26 0.10.8 yl)methyl]-5-(2-propoxy-3- pyridyl)pyrazolo[4,3-b]pyridin-7-amine143 1-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)- 3.8 0.26 9.2N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine 1445-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 14 1.1 23methylpropyl]-N-(1H-1,2,4-thazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 1451-isopropyl-3-methyl-N-[(1-methyl-1,2,4- 0.41 0.095 1.2thazol-3-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine 1461-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)- 3.9 0.51 14N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine 1471-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 12 2.1 28yl)methyl]-5-thiazol-2-yl-pyrazolo[4,3- b]pyridin-7-amine 1481-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 110 58 86yl)methyl]-5-(5-methylthiazol-2- yl)pyrazolo[4,3-b]pyridin-7-amine 1491-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 29 2.4 69yl)methyl]-5-(4-methylthiazol-2- yl)pyrazolo[4,3-b]pyridin-7-amine 1503-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4- 44 33 13yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-5- methyl-oxazolidin-2-one151 3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4- 10 4.7 12yl)methylamino]pyrazolo[4,3-b]pyridin-5- yl]oxazolidin-2-one 1521-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4- 48 32 61yl)methylamino]pyrazolo[4,3-b]pyridin-5- yl]azetidin-2-one 1531-tert-butyl-3-[1-isopropyl-3-methyl-7-[(1- 130 76 270methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]imidazolidin-2-one 1541-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4- 26 3.6 49yl)methylamino]pyrazolo[4,3-b]pyridin-5- yl]pyrrolidin-2-one 1553-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4- 8.2 4.9 3.9yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-4- methyl-oxazolidin-2-one156 4-ethyl-3-[1-isopropyl-3-methyl-7-[(1- 31 31 5.1methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]oxazolidin-2-one 157N-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3- 34 14 77methyl-pyrazolo[4,3-b]pyridin-7-yl]methyl]-5- methoxy-pyridin-3-amine158 N-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3- 23 4.9 50methyl-pyrazolo[4,3-b]pyridin-7-yl]methyl]-1-methyl-1,2,4-triazol-3-amine 1595-(2-ethoxy-3-pyridyl)-1-isopropyl-7-[2-(5- 270 70 1600methoxy-3-pyridyl)ethyl]-3-methyl- pyrazolo[4,3-b]pyridine 1605-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-7- 23 3.9 56[2-(1-methyl-1,2,4-triazol-3- yl)ethyl]pyrazolo[4,3-b]pyridine 1615-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 60 6.6 120[(2-methyl-1,2,4-triazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine 1625-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 100 13 180[(4-methyl-1,2,4-triazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine 1635-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methyl- 120 14 1201,2,4-triazol-3-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine 1645-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-7- 6.8 1.6 25[(1-methylpyrazol-4- yl)methylsulfanyl]pyrazolo[4,3-b]pyridine 165N-[[1-(difluoromethyl)pyrazol-4-yl]methyl]-5- 73 5.9 110(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine 166 5-(2-ethoxy-3-pyridyl)-N-[[5- 2.10.16 7.2 (fluoremethyl)isoxazol-3-yl]methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7- amine 1675-(2-ethoxy-3-pyridyl)-N-[[3- 11 1 33(fluoromethyl)isoxazol-5-yl]methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7- amine 1681-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 14 2.6 36yl)methyl]-5-oxazol-2-yl-pyrazolo[4,3- b]pyridin-7-amine 1691-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 610 85 170yl)methyl]-5-(3-methyltriazol-4-yl)pyrazolo[4,3- b]pyridin-7-amine 1701-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl- 42 5.3 46N-[[2-(trifluoromethyl)-3- pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine171 3-[1-isopropyl-7-[(2-methoxy-3- 290 47 420pyridyl)methylamino]-3-methyl-pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one 1725-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3- 40 5.5 46methoxy-4-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 1731-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl- 49 6.3 26N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 1745-(2-cyclopropoxypyridin-3-yl)-1-isopropyl-N- 18 1.5 522-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine 175 1-isopropyl-N-((2-methoxypyridin-3-83 17 130 yl)methyl)-3-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine 1765-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5- 81 12 93methoxypyrimidin-2-yl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine177 3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4- 130 20 180yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]- 1H-pyridin-2-one 178N-[[2-(difluoromethyl)-3-pyridyl]methyl]-5-(2- 31 3.2 63ethoxy-3-pyridyl)-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amine179 5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6- 2.8 0.51 7methoxypyrimidin-4-yl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine180 5-(2-(ethoxy-1,1-d₂)pyridin-3-yl)-1-isopropyl- 27 0.77 78N((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine 1815-(2-(ethoxy-d₅)pyridin-3-yl)-1-isopropyl-N-((2- 31 1.6 84methoxypyridin-3-yl)methyl)-3-methyl-1H- pyrazolo[4,3-b]pyridin-7-amine182 5-(2-(ethoxy-2,2,2-d₃)pyridin-3-yl)-1-isopropyl- 24 1.1 61N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine 1831-isopropyl-N-((2-methoxypyridin-3- 290 38 350 yl)methyl)-3-methyl-5-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[4,3- b]pyridin-7-amine 1843-(difluoromethyl)-5-(2-ethoxypyridin-3-yl)-1- 13 2.4 45isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine 1851-isopropyl-3-methyl-N-((1-methyl-1H- 100 24 92pyrazol-4-yl)methyl)-5-(1H-1,2,4-triazol-1-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine 1863-[1-isopropyl-3-methyl-7-[(1-methyl-1,2,4- 64 15 130triazol-3-yl)methylamino]pyrazolo[4,3- b]pyridin-5-yl]-1H-pyridin-2-one187 3-[1-isopropyl-3-methyl-7-(1H-pyrazol-3- 140 18 250ylmethylamino)pyrazolo[4,3-b]pyridin-5yl]- 1H-pyridin-2-one 1885-[2-(difluoromethoxyl)-3-pyridyl]-1-isopropy-- 61 7.8 60N-[(2-methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine189 5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4- 3.9 0.49 19methoxypyrimidin-2-yl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine190 5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4- 74 7.9 94methoxypyrimidin-5-yl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine191 5-(2-ethoxy-3-pyridyl)-N-[(2-ethoxy-3- 160 10 400pyridyl)methyl]-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 1925-[2-(dimethylamino)-3-pyridyl]-1-isopropyl-N- 630 71 490[(4-methoxyphenyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 1933-[1-isopropyl-3-methyl-7-[[2-(trifluoromethyl)- 320 54 8803-pyridyl)methylamino]pyrazolo[4,3-b]pyridin- 5-yl]-1H-pyridin-2-one 1941-isopropyl-3-methyl-5-(3-methylisoxazol-4- 95 23 21yl)-N-[(1-methylpyrazol-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine 1951-isopropyl-3-methyl-5-(1-methyl-1H-1,2,4- 420 110 160triazol-5-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine 1961-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)- 18 1.7 27N-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine 1975-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-3- 190 13 190pyridyl)methyl]-3-methyl-1-(oxetan-3- yl)pyrazolo[4,3-b]pyridin-7-amine198 5-(2-(ethyl(methyl)amino)pyridin-3-yl)-1- 1100 240 1000isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine 1995-(2-ethoxypyridin-3-yl)-3-(fluoromethyl)-1- 7.4 0.75 26isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine 2001-isopropyl-3-methyl-N-((1-methyl-1H- 98 18 110pyrazol-4-yl)methyl)-5-(4-methyloxazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine 2015-[2-(dimethylamino)-3-pyridyl]-1-isopropyl-3- 2100 230 2100methyl-N-[(1-methylpyrazol-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine202 1-isopropyl-3-methyl-N-((1-methyl-1H- 92 14 170pyrazol-4-yl)methyl)-5-(4-methyloxazol-2-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine 2031-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 410 180 420yl)methyl]-5-(4-methyl-1,2,4-triazol-3-yl)pyrazolo[4,3-b]pyridin-7-amine

Table 1 lists the IC₅₀ value for inhibition of PDE1 by the compounds ofthe invention. The IC₅₀ value refers to the concentration (nM) of thecompound required to reach 50% inhibition of the PDE1 enzyme at thespecified substrate concentration. PDE1 assays are described in theExperimental Section.

EXPERIMENTAL SECTION Preparation of the Compounds of theInvention—General Methods

The compounds of formula (I) may be prepared by methods described below,together with synthetic methods known in the art of organic chemistry,or modifications that are familiar to those of ordinary skill in theart. The starting materials used herein are available commercially ormay be prepared by routine methods known in the art, such as thosemethod described in standard reference books such as “Compendium ofOrganic Synthetic Methods, Vol. I-XIII” (published withWiley-Interscience, ISSN: 1934-4783). Preferred methods include, but arenot limited to, those described below.

The schemes are representative of methods useful in synthesizing thecompounds of the present invention. They are not to constrain the scopeof the invention in any way.

Method 1:

where R1 is as described for formula I and R is hydrogen or R is R₂ asdescribed for formula I.

Compounds of general formula IV (Scheme 1) can be prepared fromcompounds of general formula II and III.

Method 2:

where R1 is as described for formula I and R is R2 is as described forformula I or a protection group such as para-methoxy benzyl.

Compounds of general formula IV (Scheme 2) can be prepared fromcompounds of general formula II, 1l and V as described in the literature(e.g. Int. Pat. App. WO2013142307)

Method 3:

where R1 is as described for formula I, R is R2 is as described forformula I or R is a protection group such as para-methoxy benzyl and Yis a halogen such as chlorine or bromine.

Compounds of general formula VIII (Scheme 3) can be prepared bynitration of compounds of general formula IV followed by reduction.Compounds of general formula XI can be prepared by reaction of compoundsof general formula VIII with methyl 3-chloro-3-oxopropanoate followed byring-closure in the presence of a base such as sodium ethoxide or sodiummethoxide. Hydrolysis and decarboxylation of compounds of generalformula XI followed by treatment with phosphoryl trichloride orphosphoryl tribromide gives compounds of general formula XIII.

Method 4:

where R1 and R2 are as described for formula I, R is a protection groupsuch as para-methoxy benzyl, Y is a halogen such as chlorine or bromineand Z is a leaving group such as chlorine, bromine, iodine or amethanesulfonate group or Z is a hydroxy group. Compounds of generalformula XIV (Scheme 4) can be prepared by the deprotection of compoundsof general formula XIII where R is a protection group. If the protectiongroup is para-methoxy benzyl, the deprotection can be performed bytreatment with an acid such as trifluoroacetic acid. Compounds ofgeneral formula XIII can be prepared by reaction of compounds of generalformula XIV with compounds of general formula XV in the presence of abase such as cesium carbonate or using Mitsunobu reaction conditionswhen Z is a hydroxy group.

Method 5:

where R1, R2, R3 and R4 are as described for formula I, L is NH, O or Sand R are hydroxy groups or R together with the boron atom form a4,4,5,5-tetramethyl-1,3,2-dioxaborolane group. Y is a halogen such aschlorine or bromine.

Compounds of general formula XVII (Scheme 5) can be prepared bytreatment of compounds of general formula XIII with compounds of generalformula XVI in the presence of a base such as but not limited to cesiumfluoride or N,N-diisopropylethylamine.

Compounds of general formula I can be prepared from compounds of generalformulae XVII and XVIII in the presence of a palladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and abase such as potassium carbonate or other Suzuki-Miyaura couplingreaction conditions known to chemists skilled in the art of organicsynthesis.

Method 6:

where R1, R2, R3 and R4 are as described for formula I. R are hydroxygroups or R together with the boron atom form a4,4,5,5-tetramethyl-1,3,2-dioxaborolane group and Pg is a protectiongroup such as para-methoxy benzyl. Y is a halogen such as chlorine orbromine.

Compounds of general formula XX (Scheme 6) can be prepared by treatmentof compounds of general formula XIII with compounds of general formulaXIX in the presence of a base such as but not limited to cesium fluorideor N,N-diisopropylethylamine. Compounds of general formula XXI can beprepared from compounds of general formulae XX and XVIII in the presenceof a palladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and abase such as potassium carbonate or other Suzuki-Miyaura couplingreaction conditions known to chemists skilled in the art of organicsynthesis. Compounds of general formula XXII can be prepareddeprotection of compounds of general formula XXI. If the protectiongroup is para-methoxy benzyl, the deprotection can be performed bytreatment with an acid such as trifluoroacetic acid. Compounds ofgeneral formula I can be prepared by reductive amination of compounds ofgeneral formula XXII with the appropriate aldehyde or ketone.

Method 7:

where R1, R2, and R3 are as described for formula I, L is NH, O or S, Rare hydroxy groups or R together with the boron atom form a4,4,5,5-tetramethyl-1,3,2-dioxaborolane group. Y is a halogen such aschlorine or bromine.

Compounds of general formula XXIV (Scheme 7) can be prepared fromcompounds of general formulae XIII and XXIII in the presence of apalladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and abase such as potassium carbonate or other Suzuki-Miyaura couplingreaction conditions known to chemists skilled in the art of organicsynthesis. Compounds of general formula XXV can be prepared by treatmentof compounds of general formula XXIV with compounds of general formulaXVI in the presence of a base such as but not limited to cesium fluorideor N,N-diisopropylethylamine. Compounds of general formula I can beprepared by treatment of compounds of general formula XXV with sodiumethoxide.

Method 8:

where R1, R2, R3, R4 and L are as described for formula I and M is ZnClor SnR₃, where R are alkyl groups such as butyl or methyl. Y is ahalogen such as chlorine or bromine.

Compounds of general formula I (Scheme 8) can be prepared from compoundsof general formulae XVII and XXVI in the presence of a palladiumcatalyst such Pd(PPh₃)₄ or other Stille or Negishi coupling reactionconditions known to chemists skilled in the art of organic synthesis.

Method 9:

where R1, R2, R3, and L are as described for formula I and M is ZnCl orSn(R)₃, where R are alkyl groups such as butyl or methyl. Y is a halogensuch as chlorine or bromine. R4 is as described for formula I with theattachment point of R4 is a nitrogen.

Compounds of general formula I (Scheme 9) can be prepared from compoundsof general formulae XVII and XXVII in the presence of a cupper catalystsuch as Cul in combination with a ligand or palladium catalyst such asPd₂(dba)₃ in combination with Xantphos and a base such as Cs₂CO₃ usingreaction conditions known to chemists skilled in the art of organicsynthesis.

Method 10:

where R1, R2 and R4 are as described for formula I, L is CH₂ andR3 is methyl substituted with phenyl, pyridonyl, pyridinyl, pyrimidinylor pyrazinyl all of which can be optionally substituted one or moretimes with one or more substituents selected from the group consistingof halogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxyand C₁-C₃ alkoxy; or R3 is methyl substituted with a 5-memberedheteroaryl which is optionally substituted with one or more substituentsselected from halogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₅fluoroalkoxy and C₁-C₃ alkoxy. R5 is phenyl, pyridonyl, pyridinyl,pyrimidinyl or pyrazinyl all of which can be optionally substituted oneor more times with one or more substituents selected from the groupconsisting of halogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃fluoroalkoxy and C₁-C₃ alkoxy; or R5 is a 5-membered heteroaryl which isoptionally substituted with one or more substituents selected fromhalogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxy andC₁-C₅ alkoxy. Y is a halogen such as chlorine or bromine. X is a halogensuch as iodine or bromine.

Compounds of general formula XXVIII (Scheme 10) can be prepared bytreatment of compounds of general formula XIII with a reagent such asi-PrMgCl—LiCl followed by treatment with N,N-dimethyl formamide.Compounds of general formula XXIX can be prepared by treatment ofcompounds of general formula XXVIII with a reagent such as1-diazo-1-dimethoxyphosphoryl-propan-2-one and a base such as Cs₂CO₃.Compounds of general formula XXXI can be prepared from compounds ofgeneral formulae XXIX and XXX in the presence of a palladium catalystsuch as [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride,a base such as triethylamine and a cupper catalyst such as Cul usingreaction conditions known to chemists skilled in the art of organicsynthesis. Compounds of general formula I can be prepared by treatmentof compounds of general formula XXXI with palladium on carbon under anatmosphere of hydrogen.

Method 11:

where R1. R2 and R4 are as described for formula I,L is CH₂ and R3 is NH which is substituted with phenyl, pyridonyl,pyridinyl, pyrimidinyl or pyrazinyl all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of halogen, cyano, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ fluoroalkoxy and C₁-C₃ alkoxy; or L is CH₂ and R3 isNH which is substituted with a 5-membered heteroaryl which is optionallysubstituted with one or more substituents selected from halogen, cyano,C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxy and C₁-C₃ alkoxy. R5is phenyl, pyridonyl, pyridinyl, pyrimidinyl or pyrazinyl all of whichcan be optionally substituted one or more times with one or moresubstituents selected from the group consisting of halogen, cyano, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxy and C₁-C₃ alkoxy; or R5 isa 5-membered heteroaryl which is optionally substituted with one or moresubstituents selected from halogen, cyano, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ fluoroalkoxy and C₁-C₃ alkoxy. Y is a halogen such aschlorine or bromine.

Compounds of general formula XVII (Scheme 11) can be prepared byreductive amination of compounds of general formula XXVIII withcompounds of general formula XXXII.

Method 12:

where R1, R2, R3 and R4 are as described for formula I and L is sulphur.Y is a halogen such as chlorine or bromine. Pg is a protecting groupsuch as 6-methylheptyl propano-3-ate. Lg is a leaving group such aschlorine, bromine, iodine, 4-methylbenzenesulfonate or methanesulfonate.

Compounds of general formula XXXIII (Scheme 12) can be prepared bytreatment of compounds of general formula XIII with a reagent such as6-methylheptyl 3-mercaptopropanoate in the presence of a base such asdiisopropyl ethylamine. Compounds of general formula XXXIV can beprepared by the same methods as described in methods 5, 8 and 9.Compounds of general formula I can be prepared by deprotection ofcompounds of general formula XXXIV by using a base such as potassiumtert-butoxide followed by alkylation with compounds of general formulaXXXVI.

Method 13:

where R1, R2, R3 and R4 are as described for formula I and L is NH. Pgis a protecting group such as p-methoxybenzyl and Lg is a leaving groupsuch as chlorine, bromine, iodine, 4-methylbenzenesulfonate ormethanesulfonate.

Compounds of general formula XXXVII (Scheme 13) can be prepared bydeprotonation of compounds of general formula XXI with a base such assodium hydride followed by alkylation with compounds of general formulaXXXVI. Compounds of general formula I can be prepared by removal of theprotecting group (Pg) using reaction conditions known to chemistsskilled in the art of organic synthesis, e.g. by treatment withtrifluoroacetic acid when Pg is p-methoxybenzyl.

LC-MS Methods Method A:

An Agilent 1200 LCMS system with ELS detector was used. PhenomenexLuna-C18, 5 μm; 2.0×50 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=90:10 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method B:

An Agilent 1200 LCMS system with ELS detector was used. Column: WatersXBridge ShieldRP18, 2.1×50 mm, 5 μm; Column temperature: 40° C.; Solventsystem: A=water/ammonia (99.95:0.05) and B=acetonitrile; Method: Lineargradient elution with A:B=95:5 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method C:

An Agilent 1200 LCMS system with ELS detector was used. PhenomenexLuna-C18, 5 μm; 2.0×50 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=99:1 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method D:

A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEH C18 1.7 μm;2.1×50 mm; Column temperature: 60° C.; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/water/trifluoroacetic acid (94.965:5:0.035); Method:Linear gradient elution with A:B=90:10 to 0:100 in 1.0 minutes and witha flow rate of 1.2 mL/min.

Method E:

A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEH C18 1.7 μm;2.1×50 mm; Column temperature: 60° C.; Solvent system: A=water/formicacid (99.9:0.1) and B=acetonitrile/water/formic acid (94.9:5:0.1);Method: Linear gradient elution with A:B=90:10 to 0:100 in 1.0 minutesand with a flow rate of 1.2 mL/min.

Method F:

An Agilent 1200 LCMS system with ELS detector was used. Column: WatersXBridge ShieldRP18, 2.1×50 mm, 5 μm; Column temperature: 40° C.; Solventsystem: A=water/ammonia (99.95:0.05) and B=acetonitrile; Method: Lineargradient elution with A:B=85:15 to 0:100 in 3.4 minutes and with a flowrate of 0.8 mL/min.

Method G:

An Agilent 1200 LCMS system with ELS detector was used. Column: AgilentTC-C18 5 μm; 2.1×50 mm; Column temperature: 50° C.: Solvent system:A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=99:1 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method H:

An Agilent 1200 LCMS system with ELS detector was used. Column: WatersXBridge ShieldRP18, 2.1×50 mm, 5 μm; Column temperature: 40° C.; Solventsystem: A=water/ammonia (99.95:0.05) and B=acetonitrile; Method: Lineargradient elution with A:B=70:30 to 0:100 in 3.4 minutes and with a flowrate of 0.8 mL/min.

Method I:

An Agilent 1200 LCMS system with ELS detector was used. PhenomenexLuna-C18, 5 μm; 2.0×50 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=75:25 to 0:100 in 3.4 minutes and with a flowrate of 0.8 mL/min.

Method J:

A Waters Autopurification was used. Column: XSelect CSH C18 3.5 micron,4.6×50 mm; Column temperature: 25° C.; Solvent system: A=water/formicacid (99.9:0.1) and B=acetonitrile/trifluoroacetic acid (99.9:0.1);Method: Linear gradient elution with A:B=97:3 to 10:90 in 2.5 minutesand with a flow rate of 2.5 mL/min.

Method K:

A Waters Autopurification was used. Column: XSelect CSH C18 3.5 micron,4.6×50 mm; Column temperature: 25° C.; Solvent system: A=water/formicacid (99.9:0.1) and B=acetonitrile/trifluoroacetic acid (99.9:0.1);Method: Linear gradient elution with A:B=97:3 to 10:90 in 2.5 minutes,then with A:B=10:90 for 1 minute. The flow rate was 2.5 mL/min.

Intermediates: Preparation of ethyl 3-methyl-1H-pyrazole-5-carboxylate

A solution of ethyl 2,4-dioxopentanoate (20 g, 126 mmol, 18 mL) andhydrazine hydrate (6.96 g, 139 mmol, 6.76 mL) in ethanol (400 mL) wasstirred at 0° C. for 1 hour. The mixture was concentrated to give ethyl3-methyl-1H-pyrazole-5-carboxylate (19 g, 123 mmol, 97% yield).

Preparation of ethyl 1,3-dimethyl-1H-pyrazole-5-carboxylate

To a solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate (19.5 g, 126mmol) in DMF (200 mL) was added Me₂SO₄ (23.8 g, 189 mmol, 17.9 mL). Themixture was stirred at 80° C. for 18 hours. After cooling to 0° C., themixture was diluted with ice, then aqueous ammonia (25%) was added toadjust the pH to 8. Then the mixture was extracted with ethyl acetate(300 mL×3), the combined organic layers were washed with brine (50 mL),dried, and concentrated. The crude mixture was purified by flashchromatography with petroleum ether:ethyl acetate=5:1 to give ethyl1,3-dimethyl-1H-pyrazole-5-carboxylate (15 g, 89 mmol, 71% yield).

Preparation of ethyl 2-(methoxyimino)-4-oxopentanoate

A mixture of ethyl 2,4-dioxopentanoate (27 g, 171 mmol, 24 mL) andmethoxylamine (15 g, 179 mmol, 13.6 mL) in ethanol (150 mL) was stirredat 25° C. for 18 hours under a nitrogen atmosphere. The mixture wasconcentrated. The crude mixture was purified by flash silica gelchromatography with petroleum ether:ethyl acetate=10:1 to give ethyl2-(methoxyimino)-4-oxopentanoate (19.9 g, 103 mmol, 60% yield). ¹H NMR(chloroform-d 400 MHz): δ 4.34 (q, J=6.8 Hz, 2H), 4.07 (s, 3H), 3.71 (s,2H), 2.21 (s, 3H), 1.35 (d, J=7.6 Hz, 3H).

Preparation of ethyl 1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate

To a solution of ethyl 2-(methoxyimino)-4-oxopentanoate (14.6 g, 78.0mmol) in ethanol (200 mL) was added isopropylhydrazine hydrochloride(17.25 g, 156 mmol). The mixture was stirred at 80° C. for 18 hours. Themixture was concentrated. Saturated aqueous NaHCO₃ was added into theresidue to adjust the pH to 7. Then the mixture was extracted withdichloromethane (100 mL×3), the combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated. The crude mixture waspurified by flash silica gel chromatography with petroleum ether:ethylacetate=10:1 to give ethyl1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate (12.3 g, 62.7 mmol, 80%yield). ¹H NMR (chloroform-d 400 MHz): δ 6.59 (s, 1H), 5.41-5.44 (m,1H), 4.35-4.29 (m, 2H), 2.29 (s, 3H), 1.48 (d, J=6.8 Hz, 6H), 1.39-1.35(m, 3H).

Preparation of ethyl1-isopropyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylate

To a solution of ethyl 1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate (8g, 40.8 mmol) and (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (59.9g, 285.4 mmol, 39.7 mL) in TFA (80 mL) was added ammonium nitrate (6.5g, 81.5 mmol, 3.8 mL) slowly at 0° C. The mixture was stirred at 20° C.for 18 hours. The solution was cooled to 0° C. and then neutralized withaqueous K₂CO₃ and the product was extracted with ethylacetate:dichloromethane=40:1 (205 mL×4). The combined organic layerswere washed with brine (150 mL), dried over Na₂SO₄ and concentrated togive ethyl 1-isopropyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylate (9.8g).

Ethyl 1-ethyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylate was prepared ina similar way from ethylhydrazine.

Ethyl 1-cyclopropyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylate wasprepared in a similar way from cyclopropylhydrazine.

(±)-Ethyl 1-(sec-butyl)-3-methyl-1H-pyrazole-5-carboxylate was preparedin a similar way from (±)-sec-butylhydrazine hydrochloride.

Preparation of ethyl 3-methyl-4-nitro-1H-pyrazole-5-carboxylate

Ethyl 3-methyl-1H-pyrazole-5-carboxylate (12 g, 78 mmol) was added inportions to fuming nitric acid (140 g, 2.2 mol, 100 mL) at 0° C. Themixture was stirred at 15° C. for 16 hours. The mixture was poured intoice (200 g) and adjusted to pH 7 by saturated aqueous K₂CO₃. The mixturewas extracted with ethyl acetate (500 mL×2). The organic layer waswashed with H₂O (500 mL), brine (500 mL), dried over Na₂SO₄, filteredand concentrated to give ethyl3-methyl-4-nitro-1H-pyrazole-5-carboxylate (13 g, 65 mmol, 84% yield).¹H NMR (chloroform-d 400 MHz) δ 11.41 (brs, 1H), 4.47-4.42 (m, 2H), 2.64(s, 3H), 1.39 (t, J=7.2 Hz, 3H).

Preparation of ethyl1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazole-5-carboxylate and ethyl1-(4-methoxybenzyl)-5-methyl-4-nitro-1H-pyrazole-3-carboxylate

To a solution of ethyl 3-methyl-4-nitro-1H-pyrazole-5-carboxylate (4.40g, 22.1 mmol) in dry DMF (50 mL) was added1-(chloromethyl)-4-methoxybenzene (4.15 g, 26.5 mmol, 3.6 mL) and K₂CO₃(6.11 g, 44.2 mmol). The mixture was stirred at 15° C. for 16 hours. Themixture was concentrated and water (20 mL) was added. The mixture wasextracted with ethyl acetate (20 mL×2). The combined organic layers werewashed with H₂O (20 mL×2), brine (20 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by flash chromatography onsilica gel (0% to 50% ethyl acetate in petroleum ether) to give ethyl1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazole-5-carboxylate (2.80 g,8.77 mmol, 40% yield) and ethyl1-(4-methoxybenzyl)-5-methyl-4-nitro-1H-pyrazole-3-carboxylate (3.50 g,11 mmol, 50% yield).

Preparation of ethyl4-amino-1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate

To a solution of ethyl1-isopropyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylate (10.23 g, 42.41mmol) in ethyl acetate (200 mL) was added Pd—C (10%, 2.0 g, wet) undernitrogen. The suspension was degassed under vacuo and purged withhydrogen several times. The mixture was stirred under hydrogen (30 psi)at 40° C. for 18 hours. The mixture was filtered and the residue waswashed with ethyl acetate (150 ml×3), the combined filtrates wereconcentrated to give ethyl4-amino-1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate (8.96 g).

Ethyl 4-amino-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-5-carboxylate wasprepared in a similar way from ethyl1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazole-5-carboxylate.

Ethyl 4-amino-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate was prepared ina similar way from ethyl1-ethyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylate.

Ethyl 4-amino-1-cyclopropyl-3-methyl-1H-pyrazole-5-carboxylate wasprepared in a similar way from ethyl1-cyclopropyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylate.

Ethyl 4-amino-1,3-dimethyl-1H-pyrazole-5-carboxylate was prepared in asimilar way from ethyl 1,3-dimethyl-4-nitro-1H-pyrazole-5-carboxylate.

(±)-Ethyl 4-amino-1-(sec-butyl)-3-methyl-1H-pyrazole-5-carboxylate wasprepared in a similar way from (±)-ethyl1-(se-butyl)-3-methyl-1H-pyrazole-5-carboxylate.

Preparation of ethyl1-isopropyl-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylate

To a solution of ethyl4-amino-1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate (7.96 g, 37.7mmol) in dichloromethane (150 mL) was added methyl3-chloro-3-oxopropanoate (5.14 g, 37.7 mmol, 4.02 mL). The mixture wasstirred at 50° C. for 45 minutes. After the reaction mixture had cooledto room temperature, the mixture was partitioned between dichloromethane(200 mL) and saturated aqueous NaHCO₃ (100 mL), the aqueous phase wasextracted with dichloromethane (100 mL×2), the combined organic layerswere washed with brine (50 mL), dried over MgSO₄ and concentrated togive ethyl1-isopropyl-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylate(11.7 g, 37 mmol, >95% yield).

Ethyl4-(3-methoxy-3-oxopropanamido)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-5-carboxylatewas prepared in a similar way from ethyl4-amino-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-5-carboxylate.

Ethyl1-ethyl-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylatewas prepared in a similar way from ethyl4-amino-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate.

Ethyl1-cyclopropyl-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylatewas prepared in a similar way from ethyl4-amino-1-cyclopropyl-3-methyl-1H-pyrazole-5-carboxylate.

Ethyl4-(3-methoxy-3-oxopropanamido)-1,3-dimethyl-1H-pyrazole-5-carboxylatewas prepared in a similar way from ethyl4-amino-1,3-dimethyl-1H-pyrazole-5-carboxylate.

(±)-Ethyl1-(sec-butyl)-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylatewas prepared in a similar way from (±)-ethyl4-amino-1-(sec-butyl)-3-methyl-1H-pyrazole-5-carboxylate.

Preparation of methyl5,7-dihydroxy-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate

To a solution of ethyl1-isopropyl-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylate(12.5 g, 40 mmol) in ethanol (200 mL) was added NaOEt (5.45 g, 80 mmol).The mixture was stirred at 20° C. for 1 hour. The mixture wasconcentrated. The crude product (10.62 g) was used into the next stepwithout further purification.

Methyl5,7-dihydroxy-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylatewas prepared in a similar way from ethyl4-(3-methoxy-3-oxopropanamido)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-5-carboxylate.

Methyl1-ethyl-5,7-dihydroxy-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylatewas prepared in a similar way from ethyl1-ethyl-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylate.

Methyl1-cyclopropyl-5,7-dihydroxy-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylatewas prepared in a similar way from ethyl1-cyclopropyl-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylate.

Methyl5,7-dihydroxy-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate wasprepared in a similar way from ethyl4-(3-methoxy-3-oxopropanamido)-1,3-dimethyl-1H-pyrazole-5-carboxylate.

(±)-Methyl1-(sec-butyl)-5,7-dihydroxy-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylatewas prepared in a similar way from (±)-ethyl1-(sec-butyl)-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylate.

Preparation of 1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol

A mixture of methyl5,7-dihydroxy-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate(10.62 g, 40.04 mmol) in aqueous NaOH (2 N, 150 mL) was stirred at 110°C. for 6 hours. The mixture was cooled to 0° C., then saturated aqueousKHSO₄ was added to adjust the pH to 2-3. The resulting mixture wasfiltered and the residue was washed with water (50 mL×3), then dried togive 1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol (7 g,32.43 mmol, 81% yield). ¹H NMR (DMSO-d₆ 400 MHz) δ 11.02 (brs, 1H), 5.50(s, 1H), 5.11-5.08 (m, 1H), 2.24 (s, 3H), 1.37 (d, J=6.8 Hz, 6H).

1-(4-Methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol wasprepared in a similar way from methyl5,7-dihydroxy-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate.

1-ethyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol was prepared in asimilar way from methyl1-ethyl-5,7-dihydroxy-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate.

1-cyclopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol was preparedin a similar way from methyl1-cyclopropyl-5,7-dihydroxy-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate.

1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol was prepared in asimilar way from1-cyclopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol.

(±)-1-(sec-Butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol wasprepared in a similar way from (±)-methyl1-(sec-butyl)-5,7-dihydroxy-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate.

Preparation of5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine

A mixture of 1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol(3.50 g, 16.9 mmol) in phosphoryl trichloride (30 mL) was stirred at 80°C. for 18 hours. The mixture was stirred at 85° C. for another 1 hour.The mixture was concentrated and then water (50 mL) was added slowly,followed by saturated aqueous NaHCO₃ to adjust pH to 7. The aqueousphase was extracted with ethyl acetate (70 mL×3), the combined organiclayers were washed with brine (50 mL), dried over Na₂SO₄ andconcentrated. The crude product was purified by flash chromatographywith petroleum ether:ethyl acetate=20:1 to give5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine (3.50 g,14.3 mmol, 85% yield). ¹H NMR (chloroform-d 400 MHz) δ 7.28 (s, 1H),5.48-5.41 (m, 1H), 2.62 (s, 3H), 1.57 (d, J=4.8 Hz, 6H).

The following compounds were prepared in a similar manner:

5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine from1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol and phosphoryltribromide. ¹H NMR (chloroform-d 400 MHz) δ 7.60 (s, 1H), 5.61-5.55 (m,1H), 2.63 (s, 3H), 1.57 (d, J=6.4 Hz, 6H).

5,7-dibromo-1-ethyl-3-methyl-1H-pyrazolo[4,3-b]pyridine from1-ethyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol and phosphoryltribromide.

5,7-dichloro-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine from1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol and phosphoryltrichloride. ¹H NMR (chloroform-d 400 MHz) δ 7.29 (s, 1H), 4.29 (s, 3H),2.60 (s, 3H).

(±)-5,7-Dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine from(±)-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol andphosphoryl tribromide.

5,7-dibromo-1-cyclopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine from1-cyclopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol andphosphoryl tribromide. ¹H NMR (chloroform-d 400 MHz) δ 7.63 (s, 1H),3.99-3.88 (m, 1H), 2.57 (s, 3H), 1.41-1.38 (m, 2H), 1.22-1.19 (m, 2H).

5,7-Dibromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine from1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol andphosphoryl tribromide.

Preparation of 5,7-dibromo-3-methyl-1H-pyrazolo[4,3-b]pyridine

A solution of5,7-dibromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine (650mg, 1.58 mmol) in TFA (5 mL) was heated at 80° C. for 2 hours. Themixture was concentrated and the residue was dissolved in H₂O (5 mL).The mixture was adjusted to pH 7 by saturated aqueous. NaHCO₃ andextracted with ethyl acetate (20 mL×2). The combined organic layers werewashed with H₂O (20 mL), brine (20 mL), dried over Na₂SO₄, filtered andconcentrated to give 5,7-dibromo-3-methyl-1H-pyrazolo[4,3-b]pyridine(450 mg, 1.55 mmol, 98% yield).

Preparation of5,7-dibromo-3-methyl-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridine

To a solution of 5,7-dibromo-3-methyl-1H-pyrazolo[4,3-b]pyridine (340mg, 1.17 mmol) in dry DMF (10 mL) was added 3-iodooxetane (323 mg, 1.76mmol) and Cs₂CO₃ (762 mg, 2.34 mmol). The mixture was heated undermicrowave at 100° C. for 1 hour. The mixture was concentrated and water(20 mL) was added. The mixture was extracted with ethyl acetate (20mL×2). The combined organic layers were washed with H₂O (20 mL×2), brine(20 mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on silica gel (0% to 50% ethyl acetatein petroleum ether) to give5,7-dibromo-3-methyl-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridine (200 mg,49% yield).

Preparation of(−)-5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine and(+)-5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine

(±)-5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine (2.2g, 6.34 mmol) was purified by SFC twice to give(+)-5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine (800mg) (Rt=6.25 min) and(−)-5,7-dibromo-1-(se-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine (900mg) (Rt=6.28 min).

(+)-5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine ¹H NMR(Chloroform-d, 400 MHz): δ 7.60 (s, 1H), 5.41-5.32 (m, 1H), 2.63 (s,3H), 2.13-2.07 (m, 1H), 1.87-1.83 (m, 1H), 1.54 (d, J=6.4 Hz, 3H), 0.79(t, J=7.6 Hz, 3H). SFC-MS: t_(R)=6.25 min, ee %=100%; [α]_(D) ²⁰=2.60(c=1.0, dichloromethane).

(−)-5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine ¹H NMR(Chloroform-d, 400 MHz): δ 7.60 (s, 1H), 5.41-5.32 (m, 1H), 2.63 (s,3H), 2.13-2.07 (m, 1H), 1.87-1.83 (m, 1H), 1.55 (d, J=6.8 Hz, 3H), 0.79(t, J=7.6 Hz, 3H). SFC-MS: t_(R)=6.5 min, ee %=97.87%; [α]_(D) ²⁰=−2.90(c=1.0, dichloromethane).

SFC Condition 1:

Instrument: Thar SFC 1; Column: (s,s) WHELK-01 (250 mm×30 mm, 5 μm);Mobile phase: A: Supercritical CO₂, B: isopropyl alcohol (0.1% NH₃H₂O),A B=85:15 at 60 ml/min; Column Temp: 38° C.; Nozzle Pressure: 100 Bar;Nozzle Temp: 60° C.; Evaporator Temp: 20° C.; Trimmer Temp: 25° C.;Wavelength: 220 nm

SFC Condition 2:

Instrument: Thar SFC-13; Column: (s,s) WHELK-01 (250 mm×30 mm, 5 μm);Mobile phase: A: Supercritical CO₂, B: isopropyl alcohol (0.1% NH₃H₂O),A B=85:15 at 60 ml/min: Column Temp: 38° C.; Nozzle Pressure: 100 Bar,Nozzle Temp: 60° C.; Evaporator Temp: 20° C.; Trimmer Temp: 25° C.:Wavelength: 220 nm

Preparation of 4,6-dibromo-2-methylpyridin-3-amine

A solution of 6-bromo-2-methylpyridin-3-amine (24 g, 128 mmol) and AcOH(14.7 mL 257 mmol) in MeOH (200 mL) was cooled to 0° C., Br₂ (36.9 g,230.9 mmol, 11.9 mL) was added and stirred at 0° C. for 5 hours. Themixture was quenched with saturated aqueous Na₂SO₃ (500 mL), extractedwith ethyl acetate (300 mL×3). The organic layer was washed with brine(200 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue waspurified by silica gel chromatography (petroleum ether:ethylacetate=2:1) to afford 4,6-dibromo-2-methylpyridin-3-amine (30 g, 87%yield).

Preparation of 5,7-dibromo-1H-pyrazolo[4,3-b]pyridine

To a mixture of 4,6-dibromo-2-methylpyridin-3-amine (15.0 g, 56.4 mmol)and AcOK (13.8 g, 141 mmol) in AcOH (30 mL) and toluene (200 mL) wasadded isopentyl nitrite (13.2 g, 112.8 mmol). The mixture was stirred at25° C. for 1 hour then at 60° C. for 19 hours. The mixture wasconcentrated in vacuo, diluted with water (300 mL) and extracted withethyl acetate (200 mL×2). The organic layer was washed with brine (100mL), dried over Na₂SO₄ and concentrated in vacuo to give5,7-dibromo-1H-pyrazolo[4,3-b]pyridine (5.4 g, 30% yield).

Preparation of 5,7-dibromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine

To a mixture of 5,7-dibromo-1H-pyrazolo[4,3-b]pyridine (1 g, 3.6 mmol)and Cs₂CO₃ (12.4 g, 7.2 mmol) in anhydrous DMF (10 mL) was addediodoethane (0.8 g, 5.4 mmol). The mixture was stirred at 0° C. for 0.5hours. The mixture was diluted with water (20 mL), extracted with ethylacetate (30 mL×2). The organic layer was washed with water (20 mL),brine (20 mL) and dried with Na₂SO₄, concentrated in vacuo. The residuewas purified by silica gel chromatography (petroleum ether:ethylacetate=10:1-5:1) to give 5,7-dibromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine(0.56 g, 51% yield). ¹H NMR (DMSO-d₆ 400 MHz) δ 8.37 (s, 1H), 7.98 (s,1H), 4.72 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).

The following compounds were prepared in a similar manner:

5,7-Dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine from5,7-dibromo-1H-pyrazolo[4,3-b]pyridine and 2-iodopropane. ¹H NMR (DMSO-d400 MHz) δ 8.36 (s, 1H), 7.94 (s, 1H), 5.62-5.55 (m, 1H), 1.49 (d, J=6.0Hz, 6H).

5,7-Dibromo-1-propyl-1H-pyrazolo[4,3-b]pyridine from5,7-dibromo-1H-pyrazolo[4,3-b]pyridine and 1-iodopropane. ¹H NMR(chloroform-d 400 MHz) δ 8.14 (s, 1H), 7.64 (s, 1H), 4.67 (t, J=7.2 Hz,2H), 1.98-1.89 (m, 2H), 0.94 (t, J=7.6 Hz, 3H).

5,7-Dibromo-1-methyl-1H-pyrazolo[4,3-b]pyridine from5,7-dibromo-1H-pyrazolo[4,3-b]pyridine and iodomethane. ¹H NMR(chloroform-d 400 MHz) δ 8.13 (s, 1H), 7.64 (s, 1H), 4.38 (s, 3H).

(±)-5,7-Dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine from5,7-dibromo-1H-pyrazolo[4,3-b]pyridine and (±)-2-iodobutane.

Preparation of (+)-5,7-dibromo-1-(sec-butyl)-1H-pyrazolo[4,3-b]pyridineand (−)-5,7-dibromo-1-(sec-butyl)-1H-pyrazolo[4,3-b]pyridine

(±)-5,7-dibromo-1-sec-butyl-pyrazolo[4,3-b]pyridine (5.2 g, 15.6 mmol)was separated by SFC with column: AD (250 mm*50 mm, 10 μm); mobilephase: [0.1% NH₃H₂O in isopropyl alcohol]; B %: 20%-20%, min.

(+)-5,7-dibromo-1-(sec-butyl)-1H-pyrazolo [4,3-b]pyridine (2.5 g)(Rt=3.137 min) ([α]_(D) ²⁰=1.40) (c=1.0, ethanol).

(−)-5,7-dibromo-1-(sec-butyl)-1H-pyrazolo[4,3-b]pyridine (2.5 g)(Rt=2.808 min) ([α]_(D) ²⁰=−1.60) (c=1.0, ethanol).

Preparation of5-chloro-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

To a solution of5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine (100 mg,410 μmol) and (4-methoxyphenyl)methanamine (67 mg, 492 μmol, 64 μL) inNMP (5 mL) was added CsF (124 mg, 819 μmol, 30 μL). The mixture wasstirred at 100° C. for 18 hours. Water (20 mL) was added and the mixturewas filtered and concentrated in vacuo. The crude mixture was purifiedby flash chromatography with petroleum ether:ethyl acetate=3:1 to give5-chloro-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(80 mg, 215 μmol, 53% yield). ¹H NMR (chloroform-d 400 MHz) δ 7.32 (d,J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.39 (s, 1H), 4.79 (brs, 1H),4.70-4.63 (m, 1H), 4.39 (d, J=4.4 Hz, 2H), 3.85 (s, 3H), 2.56 (s, 3H),1.57 (d, J=6.4 Hz, 6H).

Preparation of5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

To a solution of5-chloro-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(60 mg, 174 μmol) in dioxane (2 mL) and H₂O (0.5 mL) was addedPd(1,1′-bis(diphenylphosphino)ferrocene)Cl₂ (25 mg, 35 μmol) and Cs₂CO₃(141.72 mg, 435 μmol) and (2-ethoxypyridin-3-yl)boronic acid (52 mg, 313μmol). The mixture was stirred at 100° C. for 1 hour under microwaveirradiation. Water (30 mL) was added and the mixture was extracted withethyl acetate (30 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄ and concentrated. The crude mixture waspurified by flash chromatography with petroleum ether:ethyl acetate=1:1to 0:1 to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(50 mg, 67% yield). ¹H NMR (chloroform-d 400 MHz) δ 8.27-8.25 (m, 1H),8.17-8.16 (m, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.22 (s, 1H), 7.03-7.00 (m,1H), 6.95 (d, J=8.4 Hz, 2H), 4.81-4.76 (m, 1H), 4.65 (brs, 1H),4.47-4.41 (m, 4H), 3.84 (s, 3H), 2.65 (s, 3H), 1.60 (d, J=6.4 Hz, 6H),1.36 (t, J=7.2 Hz, 3H).

The following compounds were prepared in a similar manner:

5-(2-Fluoropyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from5-bromo-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand (2-fluoropyridin-3-yl)boronic acid.

3-(1-Isopropyl-7-((4-methoxybenzyl)amino)-3-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2(1H)-one

Prepared from5-chloro-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand (2-oxo-1,2-dihydropyridin-3-yl)boronic acid.

Preparation of5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

A solution of5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(1.25 g, 2.90 mmol) in TFA (15 mL) was stirred at 60° C. for 18 hours.The mixture was concentrated and the residue was dissolved in ethylacetate (200 mL). The resulting mixture was washed with saturatedaqueous NaHCO₃ (30 mL), brine (20 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by flash chromatographywith petroleum ether:ethyl acetate=3:1 to 2:1 to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(900 mg, 96% yield).

The following compounds were prepared in a similar manner:

5-(2-Ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amine

5-(2-Ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

1-Isopropyl-3-methyl-5-(2-propoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

1-(sec-Butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1, prepared from(+)-5,7-dibromo-1-(sec-butyl)-1H-pyrazolo[4,3-b]pyridine

1-(sec-Butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2, prepared from(−)-5,7-dibromo-1-(sec-butyl)-1H-pyrazolo[4,3-b]pyridine

1-(sec-Butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1, prepared from(+)-5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine

1-(sec-Butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2, prepared from(−)-5,7-dibromo-1-(se-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine1-Isopropyl-5-(2-methoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from1-isopropyl-N-(4-methoxybenzyl)-5-(2-methoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

5-(2-(Dimethylamino)pyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from5-(2-(dimethylamino)pyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

3-(7-Amino-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2(1H)-one

Prepared from3-(1-isopropyl-7-((4-methoxybenzyl)amino)-3-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2(1H)-one

Preparation of ethyl 3-methyl-1,2,4-oxadiazole-5-carboxylate

To a solution of ethyl 2-chloro-2-oxoacetate (1 g, 13.5 mmol) andpyridine (4.27 g, 54 mmol, 4.36 mL) in dichloromethane (40 mL) was addedat 15-20° C. N′-hydroxyacetimidamide (2.40 g, 17.5 mmol, 1.96 mL). Thesolution was stirred at 50° C. for 14 hours. The reaction mixture wascooled and quenched with saturated aqueous NH₄Cl (30 mL). The aqueousphase was extracted with dichloromethane (2×50 mL). The organic phaseswere combined, washed with saturated aqueous NaHCO₃ (50 mL), dried overMgSO₄, filtered and concentrated under reduced pressure to give ethyl3-methyl-1,2,4-oxadiazole-5-carboxylate (2.80 g, 44% yield).

Preparation of (3-methyl-1,2,4-oxadiazol-5-yl)methanol

To a solution of ethyl 3-methyl-1,2,4-oxadiazole-5-carboxylate (2.10 g,13.5 mmol) in THF (10 mL) and ethanol (10 mL) was added NaBH₄ (1.02 g,26.9 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. Themixture was quenched with saturated aqueous NH₄Cl, and concentrated invacuo. The residue was dissolved in dichloromethane (50 mL) andfiltered; the filtrate was dried over Na₂SO₄ and concentrated in vacuoto give (3-methyl-1,2,4-oxadiazol-5-yl)methanol (800 mg, 52% yield).

Preparation of 3-methyl-1,2,4-oxadiazole-5-carbaldehyde

A solution of oxalyl chloride (267 mg, 2.10 mmol, 184 μL) in drydichloromethane (5 mL) was cooled to −78° C. and then DMSO (219 mg, 2.80mmol) was added. The mixture was stirred at −78° C. for 15 minutes. Asolution of (3-methyl-1,2,4-oxadiazol-5-yl)methanol (80 mg, 0.70 mmol)in dichloromethane (0.5 mL) was added at −78° C. The mixture was stirredat −78° C. for 1 hour. Then triethylamine (0.58 mL, 4.2 mmol) was addedat −78° C. The mixture was warmed to 20° C. and stirred at 20° C. for 1hour. The mixture was poured into 1 N aqueous HCl (5 mL). The mixturewas extracted with dichloromethane (20 mL×2). The combined organiclayers were washed with H₂O (20 mL), dried over Na₂SO₄, filtered andconcentrated to give 3-methyl-1,2,4-oxadiazole-5-carbaldehyde (80 mg).¹H NMR (chloroform-d 400 MHz) δ 9.97 (s, 1H), 2.55 (s, 3H).

Preparation of 1-methyl-1H-1,2,4-triazole-3-carbaldehyde

To a mixture of (1-methyl-1H-1,2,4-triazol-3-yl)methanol (400 mg, 3.54mmol) and iodobenzene diacetate (1.25 g, 3.89 mmol) in dichloromethane(10 mL) was added TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) (56mg, 354 μmol). The mixture was stirred at 15-20° C. for 2 h. The mixturewas concentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=1:2) to give1-methyl-1H-1,2,4-triazole-3-carbaldehyde (300 mg, 2.70 mmol, 76%yield). ¹H NMR (chloroform-d 400 MHz) δ 10.01 (s, 1H), 8.19 (s, 1H),4.06 (s, 3H).

Preparation of ethyl 2-(2-acetylhydrazinyl)-2-oxoacetate

To a solution of acetohydrazide (5 g, 67 mmol) in dichloromethane (150mL) was added N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (16.7 g, 67mmol). The mixture was stirred at 15° C. for 10 minutes. Then ethyl2-chloro-2-oxoacetate (9.22 g, 67.5 mmol, 7.56 mL) was dropwise added tothe mixture. The mixture was stirred at 15° C. for 16 hours. The mixturewas washed with H₂O (100 mL) and extracted with dichloromethane (100mL×3). The combined organic phases were dried over Na₂SO₄ andconcentrated under vacuo. The residue was purified with columnchromatography (SiO₂, petroleum ether:ethyl acetate=1:0 to 0:1) to giveethyl 2-(2-acetylhydrazinyl)-2-oxoacetate (9.30 g, 79% yield).

Preparation of ethyl 5-meth-1,3,4-thiadiazole-2-carboxylate

To a solution of ethyl 2-(2-acetylhydrazinyl)-2-oxoacetate (3 g, 17mmol) in THF (100 mL) was added Lawesson's reagent (7.66 g, 19 mmol).The mixture was stirred at 75° C. for 3 hours. The mixture was dilutedwith ethyl acetate (500 mL) and added approximately 40 g ofdecolourising charcoal. The mixture was stirred at 18° C. for 16 hours.The mixture was filtered. The filtrate was concentrated under vacuo. Theresidue was purified with column chromatography (SiO₂, petroleumether:ethyl acetate=3:7) to give ethyl5-methyl-1,3,4-thiadiazole-2-carboxylate (921 mg, 28% yield).

Preparation of 5-methyl-1,3,4-thiadiazole-2-carbaldehyde

To a solution of ethyl 5-methyl-1,3,4-thiadiazole-2-carboxylate (400 mg,2.32 mmol) in dry THF (5 mL) was dropwise added DIBAL-H(diisobutylaluminium hydride) (1 M in toluene, 6.97 mL). The mixture wasstirred at −40° C. for 2 hours. The mixture was quenched with saturatedaqueous NH₄Cl (5 mL) and filtered. The solution was extracted withdichloromethane (15 mL×3). The combined organic phases were dried overNa₂SO₄ and concentrated under vacuo. The residue was purified withpreparative TLC (petroleum ether:ethyl acetate=1:1) to give5-methyl-1,3,4-thiadiazole-2-carbaldehyde (123 mg, 41% yield). ¹H NMR(chloroform-d 400 MHz) δ 10.19 (s, 1H), 2.92 (s, 3H).

Preparation of (5-methylthiophen-3-yl)methanol

To a solution of 5-methylthiophene-3-carboxylic acid (300 mg, 2.11 mmol)in THF (10 mL) was added LiAlH₄ (120 mg, 3.17 mmol) slowly at 0° C. Themixture was stirred at 20° C. for 2 hours. Water (0.3 mL) was added at0° C. to quench the reaction mixture followed by addition of 15% aqueousNaOH (0.3 mL). Ethyl acetate (50 mL) was added to the mixture, themixture was filtered and the residue was washed with ethyl acetate (20mL×2). The combined filtrates were dried over Na₂SO₄ and concentrated togive (5-methylthiophen-3-ylmethanol (270 mg).

Preparation of (5-methyloxazol-2-yl)methanol

To the reaction mixture of ethyl 5-methyloxazole-2-carboxylate (500 mg,3.22 mmol) in ethanol (10 mL) was added NaBH₄ (609 mg, 16.10 mmol) withstirring at 20° C. Then resulting solution was stirred at 20° C. for 3hours. The reaction was quenched by water (50 mL), then concentratedunder reduced pressure to remove the ethanol. The residue was extractedby ethyl acetate (50 mL×3). The combined organic layers were washed withbrine (10 mL), dried over Na₂SO₄, concentrated to give(5-methyloxazol-2-yl)methanol (364 mg).

Preparation of 5-methylthiophene-3-carbaldehyde

To a solution of (5-methylthiophen-3-yl)methanol (270 mg, 2.11 mmol) indichloromethane (10 mL) was added Dess-Martin reagent(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one) (1.07 g, 2.53mmol). The mixture was stirred at 20° C. for 1 hour. The mixture wasfiltered and the residue was washed with dichloromethane (30 mL), thecombined organic layers were concentrated. The crude mixture waspurified by flash chromatography with petroleum ether ethyl acetate=5:1to give 5-methylthiophene-3-carbaldehyde (180 mg, 1.43 mmol, 68% yield).¹H NMR (chloroform-d 400 MHz) δ 9.81 (s, 1H), 7.89 (s, 1H), 7.20 (s,1H), 2.51 (s, 3H).

The following compounds were prepared in a similar manner.

-   5-methyloxazole-2-carbaldehyde from (5-methyloxazol-2-yl)methanol-   3-methylisoxazole-5-carbaldehyde from    (3-methylisoxazol-5-yl)methanol-   5-methyl-1,2,4-oxadiazole-3-carbaldehyde from    (5-methyl-1,2,4-oxadiazol-3-yl)methanol-   1,5-dimethyl-1H-pyrazole-3-carbaldehyde from    (1,5-dimethyl-1H-pyrazol-3-yl)methanol

Preparation of 1-((1-aminoethyl)thio)-3-chloropropan-2-one

A solution of ethanethioamide (1 g, 13.3 mmol) in acetone (7 mL) wasadded dropwise to a solution of 1,3-dichloropropan-2-one (1.69 g, 13.3mmol, 1.66 mL) in acetone (5 mL) at 20° C. and stirred at 20° C. for 12hours. The mixture was filtered and the filter cake was washed withacetone (10 mL×3) to give 1-((1-aminoethyl)thio)-3-chloropropan-2-one.

Preparation of 4-(chloromethyl)-2-methylthiazole

A mixture of 1-((1-aminoethyl)thio)-3-chloropropan-2-one (3 g, 17.9mmol) in ethanol (30 mL) was stirred at 80° C. for 2 h. The mixture wasconcentrated in vacuo to give 4-(chloromethyl)-2-methylthiazole (2.9 g).

Preparation of 2-((2-methylthiazol-4-yl)methyl)isoindoline-1,3-dione

To a mixture of 4-(chloromethyl)-2-methylthiazole (2.80 g, 19.0 mmol)and isoindoline-1,3-dione in anhydrous DMF (30 mL) was added K₂CO (1.31g, 9.49 mmol). The mixture stirred at 100° C. for 0.5 hour. The mixturewas diluted with water (50 mL), extracted with ethyl acetate (50 mL×2).The organic layer was washed with water (30 mL), brine (30 mL), driedwith Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel chromatography (petroleum ether:ethyl acetate=10:1-2:1) togive 2-((2-methylthiazol-4-yl)methylisoindoline-1,3-dione (3.29 g).

Preparation of (2-methylthiazol-4-yl)methanamine

A mixture of 2-((2-methylthiazol-4-yl)methyl)isoindoline-1,3-dione (1 g,3.87 mmol) and hydrazine hydrate (291 mg, 5.81 mmol, 282 μL) in ethanol(10 mL) was stirred at 20° C. for 0.5 hour. The mixture was concentratedin vacuo. The residue was purified by silica gel chromatography(dichloromethane:methanol=0:1 to 10:1) to give(2-methylthiazol-4-yl)methanamine (330 mg).

Preparation of Benzyl (Cyanomethyl)Carbamate

A mixture of 2-aminoacetonitrile hydrochloride (5 g, 54.0 mmol), NaHCO₃(18.16 g, 216 mmol) and dioxane (50 mL) in H₂O (100 mL) was stirred at0° C. Then a solution of benzyl carbonochloridate (11.06 g, 64.8 mmol,9.22 mL) in toluene (10 mL) was added at 0° C. and stirred at 20° C. for12 hours. The mixture was poured into water (100 mL), and the aqueousphase was extracted with ethyl acetate (100 mL×3). The combined organicphases were washed with brine (100 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel chromatography to give benzyl (cyanomethyl)carbamate (1.70 g). ¹HNMR (chloroform-d 400 MHz): 7.40-7.31 (m, 5H), 5.35-5.13 (m, 3H),4.16-4.12 (m, 2H).

Preparation of benzyl ((2H-tetrazol-5-yl)methyl)carbamate

A mixture of benzyl (cyanomethyl)carbamate (200 mg, 1.05 mmol), sodiumazide (250 mg, 3.85 mmol) zinc dibromide (118 mg, 525 μmol) andisopropyl alcohol (2 mL) in H₂O (4 mL) was stirred at 100° C. for 24hours. The mixture was poured into water (50 mL), and added KHSO₄ (aq.)until pH=2. The aqueous phase was extracted with ethyl acetate (20mL×3). The combined organic phases were washed with brine (10 mL), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by silica gel chromatography (petroleum ether/ethylacetate=10/1 to 3/1) to give benzyl ((2H-tetrazol-5-yl)methyl)carbamate(200 mg).

Preparation of benzyl ((2-methyl-2H-tetrazol-5-yl)methyl)carbamate

To a mixture of benzyl ((2H-tetrazol-5-yl)methyl)carbamate (1 g, 4.29mmol) and K₂CO₃ (1.19 g, 8.58 mmol) in DMF (20 mL) was added CH₃ (0.91g, 6.4 mmol) at 0° C., and the reaction mixture was stirred at 30° C.for 12 hours. The mixture was filtrated and the filtrate wasconcentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=10/1 to 3/1) to givebenzyl ((2-methyl-2H-tetrazol-5-yl)methyl)carbamate (400 mg).

Preparation of (2-methyl-2H-tetrazol-5-yl)methanamine

To a solution of benzyl ((2-methyl-2H-tetrazol-5-yl)methyl)carbamate(250 mg, 1.0 mmol) in MeOH (10 mL) was added Pd/C (10%, wet) (10 mg)under N₂. The suspension was degassed in vacuo and purged with H₂several times. The mixture was stirred under H₂ (15 psi) at 25° C. for12 hours. The mixture was filtered and the filtrate was concentratedunder vacuum to give (2-methyl-2H-tetrazol-5-yl)methanamine (120 mg,crude).

Preparation of m-tolylmethanamine hydrochloride

A mixture 3-methylbenzaldehyde mg, 4.16 mmol, 490.20 μL) in NH₂/MeOH (7M, 1 mL) was stirred at 80° C. for 14 hours. Then NaBH₄ (315 mg, 8.32mmol) was added and the reaction mixture was stirred at 20° C. for 1hour. The mixture was diluted with water (20 mL) and extracted withethyl acetate (20 mL×2). The organic layers were washed with water (10mL), brine (10 mL), dried with Na₂SO₄ and concentrated in vacuo. Theresidue was purified by preparative HPLC to give m-tolylmethanamine (370mg) as the HCl salt.

Preparation of p-Tolylmethanol

To a suspension of LiAlH₄ (5.56 g, 147 mmol) in anhydrous THF (100 mL)was added a solution of methyl 4-methylbenzoate (11 g, 73.3 mmol) inanhydrous THF (50 mL), and the resulting mixture was stirred at 0° C.for 1 hour. The reaction mixture was quenched by addition H₂O (5 mL),15% aqueous NaOH (5 mL) and H₂O (8 mL) at 0° C., 8 g of anhydrous Na₂SO₄was added and the reaction mixture was filtered. The filtered cake waswashed with additional THF (80 mL×3). The combined organic layers wereconcentrated to give p-tolylmethanol (8.30 g, 93% yield). ¹H NMR(chloroform-d 400 MHz) δ 7.26 (d, J=8.0 Hz, 2H), 7.18 (d, J=7.6 Hz, 2H),4.65 (d, J=5.2 Hz, 2H), 2.36 (s, 3H).

Preparation of 1-(bromomethyl)-4-methylbenzene

To a solution of p-tolylmethanol (8.30 g, 68 mmol) in dichloromethane(200 mL) was added tribromophosphine (20.2 g, 74.7 mmol). The mixturewas stirred at 0° C. for 1 hour. The reaction mixture was poured intoH₂O (10 mL) and extracted with dichloromethane (25 mL), The organicphase was separated, washed with brine (10 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give1-(bromomethyl)-4-methylbenzene (12.5 g, 99% yield). ¹H NMR(chloroform-d 400 MHz) δ 7.29 (d, J=7.6 Hz, 2H), 7.16 (d, J=7.6 Hz, 2H),4.50 (s, 2H), 2.36 (s, 3H).

Preparation of 2-(4-methylbenzyl)isoindoline-1,3-dione

To a solution of 1-(bromomethyl)-4-methylbenzene (5 g, 27 mmol) in DMF(30 mL) was added potassium 1,3-dioxoisoindolin-2-ide (7.51 g, 40.5mmol). The mixture was stirred at 100° C. for 14 hours. The reactionmixture was concentrated under reduced pressure to remove DMF. Theresidue was purified by column chromatography (SiO₂, petroleumether:ethyl acetate=0 to 20%) to give2-(4-methylbenzyl)isoindoline-1,3-dione (5.50 g, 81% yield). ¹H NMR(chloroform-d 400 MHz) δ 7.85 (d, J=3.2 Hz, 2H), 7.84 (d, J=3.2 Hz, 2H),7.34 (d, J=7.6 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 4.82 (s, 2H), 2.32 (s,3H).

Preparation of p-Tolylmethanamine

To a mixture of 2-(4-methylbenzyl)isoindoline-1,3-dione (1 g, 3.8 mmol)and hydrazine hydrate (752 mg, 15 mmol, 730 μL) in MeOH (10 mL) wasstirred at 20° C. for 3 hours. The mixture was concentrated in vacuo.The residue was purified by silica gel chromatography(dichloromethane:methanol (with 5% ammonia in water)=0:1 to 5:1) to givep-tolylmethanamine (160 mg).

Preparation of ethyl 5-methyl-1,2,4-oxadiazole-3-carboxylate

To a solution of hydroxylamine hydrochloride (1.71 g, 24.6 mmol) inacetic acid (10 mL) was added ethyl carbonocyanidate (2.00 g, 20.18mmol, 1.98 mL, 1.00 eq) and NaOAc (2.02 g, 24.62 mmol, 1.22 eq) at roomtemperature and the reaction mixture was for stirred 0.5 hours. To thereaction mixture was added acetic anhydride (3.25 mL, 34.7 mmol) at roomtemperature and the reaction mixture was stirred for 0.5 hours. Then itwas stirred at 100° C. for 12 hours. The mixture was cooled to roomtemperature, and acetic acid was removed under vacuo. Ethyl acetate (25mL) and water (5 mL) were added to the reaction mixture. The solutionwas neutralized with K₂CO₃ (aq.) to pH 7. The aqueous phase wasextracted with ethyl acetate (5 mL×3). The combined organic phases werewashed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by preparative HPLC togive ethyl 5-methyl-1,2,4-oxadiazole-3-carboxylate (1.40 g).

Preparation of (5-methyl-1,2,4-oxadiazol-3-yl)methanol

To a solution of 5-methyl-1,2,4-oxadiazole-3-carboxylate (400 mg, 2.56mmol) in THF (4 mL) and ethanol (4 mL) was added NaBH₄ (290 mg, 7.68mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. Thereaction was quenched with NH₄Cl, and the mixture was concentrated undervacuo. The residue was purified by silica gel chromatography (petroleumether:ethyl acetate=1/0 to 1/1) to give(5-methyl-1,2,4-oxadiazol-3-yl)methanol (250 mg).

Preparation of 5-methyl-1,2,4-oxadiazole-3-carbaldehyde

A solution of (5-methyl-1,2,4-oxadiazol-3-yl)methanol (250 mg, 2.19mmol) and Dess-Martin periodinane (1.39 g, 3.29 mmol) in dichloromethane(5 mL) was stirred at room temperature for 12 hours. The mixture wasfiltered and the filtrate was concentrated under vacuo to give5-methyl-1,2,4-oxadiazole-3-carbaldehyde (300 mg).

Preparation of Methyl (Tert-Butoxycarbonyl)Glycinate

To a solution of methyl glycinate (20 g, 159.30 mmol) in dioxane (120mL) and water (80 mL) was added Na₂CO₃ (33.77 g, 318.60 mmol) at 0° C.,Boc₂O (43.9 mL, 191 mmol) was added dropwise at room temperature. Themixture was stirred at room temperature for 18 h. The mixture wasconcentrated, water (200 mL) was added and the mixture was extractedwith ethyl acetate (100 mL×3). The organic layer was washed with water(50 mL×2) and brine (50 mL×2), dried with anhydrous Na₂SO₄, filtered,concentrated to give methyl (tert-butoxycarbonyl)glycinate (30 g) whichwas used for next step directly.

Preparation of tert-butyl (2-hydrazinyl-2-oxoethyl)carbamate

A mixture of methyl (tert-butoxycarbonyl)glycinate (10 g, 52.9 mmol) andhydrazine hydrate (4.37 mL, 89.85 mmol) in methanol (60 mL) and water(15 mL) were stirred at room temperature for 48 hours. The mixture wasconcentrated to give tert-butyl (2-hydrazinyl-2-oxoethyl)carbamate (10g).

Preparation of tert-butyl ((1,3,4-oxadiazol-2-yl)methyl)carbamate

To a solution of tert-butyl (2-hydrazinyl-2-oxoethyl)carbamate (5.00 g,26.4 mmol) in trimethoxymethane (50 mL) was added4-methylbenzenesulfonic acid (45.5 mg, 0.26 mmol). The mixture wasstirred at 80° C. for 4 hour. The mixture was concentrated. The crudemixture was purified by flash chromatography with petroleum ether:ethylacetate=3:1 to give tert-butyl ((1,3,4-oxadiazol-2-yl)methyl)carbamate(850 mg).

Preparation of (1,3,4-oxadiazol-2-yl)methanamine hydrobromide

A solution of tert-butyl ((1,3,4-oxadiazol-2-yl)methyl)carbamate (450mg, 2.26 mmol, 1.00 eq) in 35% hydrobromic acid in acetic acid (5 mL)was stirred at room temperature for 2 hours. The mixture wasconcentrated to give (1,3,4-oxadiazol-2-yl)methanamine hydrobromide (406mg).

Preparation of methyl 1,2,4-oxadiazole-3-carboxylate

To a solution of ethyl 2-amino-2-(hydroxyimino)acetate (1.90 g, 14.4mmol) in triethoxymethane (9.58 mL, 57.5 mmol) was added BF₃.Et₂O (0.089mL, 0.72 mmol). The mixture was heated at 90° C. for 2 hours. Themixture was concentrated and the residue was dissolved indichloromethane (30 mL). The organic layer was washed with 2N HCl (aq)(20 mL), Saturated aqueous NaHCO₃ (20 mL), water (20 mL), brine (20 mL)and dried over Na₂SO₄, filtered and concentrated to give methyl1,2,4-oxadiazole-3-carboxylate (1.60 g).

Preparation of (1,2,4-oxadiazol-3-yl)methanol

To a cooled (0° C.) solution of methyl 1,2,4-oxadiazole-3-carboxylate(300 mg, 2.11 mmol) in ethanol (2 mL) and THF (2 mL) was added NaBH₄(239 mg, 6.33 mmol). The mixture was stirred at 0° C. for 1 hour.Saturated aqueous NH₄Cl (5 mL) was added, the mixture was concentratedand the residue was dissolved in 10% methanol in dichloromethane (20mL).

The mixture was filtered and the filtrate was concentrated. The residuewas purified by flash chromatography on silica gel (10%-100% ethylacetate in petroleum ether) to give (1,2,4-oxadiazol-3-yl)methanol (40mg).

Preparation of 1,2,4-oxadiazole-3-carbaldehyde

To a cooled (0° C.) solution of (1,2,4-oxadiazol-3-yl)methanol (40 mg,0.40 mmol) in dichloromethane (5 mL) was added Dess-Martin periodinane(254 mg, 0.60 mmol). The mixture was stirred at room temperature for 1hour. The mixture was filtered and the filtrate was concentrated to give1,2,4-oxadiazole-3-carbaldehyde (39 mg).

Preparation of ethyl (5-methyl-1H-1,2,4-triazol-3-yl)methanol

To a mixture of ethyl 5-methyl-1H-1,2,4-triazole-3-carboxylate (200 mg,1.29 mmol) in THF (5 mL) was added LiAlH₄ (245 mg, 6.45 mmol) at 0° C.under N₂. The mixture was stirred at 30° C. for 1 hour. The mixture wasfiltrated and washed with methanol, concentrated in vacuo to give(5-methyl-1H-1,2,4-triazol-3-yl)methanol (350 mg).

Preparation of 5-methyl-1H-1,2,4-triazole-3-carbaldehyde

To a mixture of (5-methyl-1H-1,2,4-triazol-3-yl)methanol (350 mg, 3.09mmol) in dichloromethane (10 mL) and acetonitrile (10 mL) was addedDess-Martin periodinane (2.62 g, 6.19 mmol). The mixture was stirred at30° C. for 14 hours. The mixture was filtrated and washed with petroleumether and ethyl acetate and concentrated in vacuo to give5-methyl-1H-1,2,4-triazole-3-carbaldehyde (90 mg).

Preparation of 4-bromo-6-chloro-2-methylpyridin-3-amine

To an ice cold solution of 6-chloro-2-methylpyridin-3-amine (12 g, 84mmol) and AcOH (5.1 g, 84 mmol) in MeOH (198 g, 250 mL) was dropwiseadded bromine (13.5 g, 84 mmol). The resulting solution was stirred atice bath temperature overnight after which it was concentrated undervacuo. The obtained residue was dissolved in EtOAc and sequentiallywashed with saturated aqueous NaHCO₃ solution, 10% Na₂S₂O₃ aqueoussolution, brine and dried (Na₂SO₄). The solvent was removed under vacuoand the obtained crude material was purified by flash chromatography toafford 4-bromo-6-chloro-2-methylpyridin-3-amine (12.6 g). ¹H NMR (500MHz, Chloroform-d) δ 7.30 (s, 1H), 4.04 (brs, 2H), 2.46 (s, 3H).

Preparation of 7-bromo-5-chloro-1H-pyrazolo[4,3-b]pyridine

Isopentyl nitrite (3.97 g, 33.9 mmol) was dropwise added to an ice coldsuspension of 4-bromo-6-chloro-2-methylpyridin-3-amine (5 g, 22.6 mmol),KOAc (4.43 g, 45.2 mmol) and AcOH (44.1 g, 734 mmol) in toluene (125 mL)under an inert atmosphere. A reflux condenser was inserted and thereaction mixture was heated at 30° C. over 4 h, after which most of thesolvent was removed under vacuo. The obtained residue was dissolved inethyl acetate and carefully washed with saturated aqueous NaHCO₃solution ensuring that pH 8-9 was obtained. The organic layer was washedwith brine, dried (Na₂SO₄) and concentrated to a crude material whichwas purified by flash chromatography (SiO₂) to deliver7-bromo-5-chloro-1H-pyrazolo[4,3-b]pyridine (2.3 g, 44% yield). ¹H NMR(500 MHz, Chloroform-d) δ 10.61 (brs, 1H), 8.35 (s, 1H), 7.60 (s, 1H)

Preparation of7-bromo-5-chloro-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridine

Diisopropyl azodicarboxylate (979 mg, 4.84 mmol) was dropwise added toan ice cold solution of 7-bromo-5-chloro-1H-pyrazolo[4,3-b]pyridine (250mg, 1.08 mmol), triphenylphosphine (1.27 g, 4.84 mmol) and oxetan-3-ol(319 mg, 4.30 mmol) in THF (10 mL) under an inert atmosphere. The icebath was allowed to warm to room temperature and stirring continued atroom temperature overnight. Most of the solvent was removed under vacuoand the crude material obtained was purified by flash chromatographydelivering 7-bromo-5-chloro-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridine(130 mg, 38% yield). ¹H NMR (Chloroform-d, 500 MHz) δ 8.31 (s, 1H), 7.56(s, 1H), 6.48 (p, J=6.9 Hz, 1H), 5.35 (t, J=6.5 Hz, 2H), 5.11 (t, J=7.1Hz, 2H).

Preparation of 3-(1,3-dioxolan-2-yl)pyridine

A solution of nicotinaldehyde (1 g, 9.34 mmol) in toluene (20 mL) wasadded toluene-4-sulfonic acid (1.93 g, 11 mmol) and stirred at 120° C.for 0.5 hour. Ethane-1,2-diol (637 mg, 10 mmol) was added and theresulting solution was stirred at 120° C. for 15 hours. The solution wasquenched with saturated aqueous NaHCO₃ (60 mL) and the aqueous phase wasextracted with DCM (30 mL×3). The combined organic phases were washedwith brine, dried with Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography (petroleum ether:ethylacetate=10:1 to 1:1) to give 3-(1,3-dioxolan-2-yl)pyridine (1.30 g, 92%yield). ¹H NMR (Chloroform-d, 400 MHz) δ 8.70 (d, J=2.0 Hz, 1H),8.61-8.60 (m, 1H), 7.79-7.77 (m, 1H), 7.32-7.29 (m, 1H), 5.84 (s, 1H),4.12-4.01 (m, 4H).

Preparation of 5-(1,3-dioxolan-2-yl)-1-methylpyridin-2(1H)-one

Dimethyl sulfate (1 g, 7.9 mmol) was slowly added dropwise to3-(1,3-dioxolan-2-yl)pyridine (1.20 g, 7.94 mmol) and stirred at 100° C.for 1 hour. The resulting solution was dissolved in H₂O (4 mL) and anaqueous solution of K₃[Fe(CN)₆] (6.27 g) in H₂O (24 mL) was added understirring and cooling. KOH (3.56 g) was added slowly, keeping thetemperature at 5° C. After adding DCM (12 mL), the solution was stirredat 20° C. for 0.5 hours, before additional portions of K₃[Fe(CN)₆] (3.1g) in H₂O (11 mL) and KOH (1.8 g) were added at 20° C. and stirred at20° C. for 12 hours. The aqueous phase was extracted with ethyl acetate(30 mL×3). The combined organic phases were washed with brine, driedwith Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by preparative HPLC to give5-(1,3-dioxolan-2-yl)-1-methylpyridin-2(1H)-one (250 mg).

Preparation of 1-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde

A solution of 5-(1,3-dioxolan-2-yl)-1-methylpyridin-2(1H)-one (250 mg,1.38 mmol) in 3% aqueous HCl (5 mL) was stirred at 100° C. for 3 hours.The solution was extracted with DCM (10 mL×3). The combined organicphases were washed with brine, dried with Na₂SO₄, filtered andconcentrated in vacuo to give1-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde (150 mg).

Preparation of 6-(difluoromethyl)nicotinaldehyde

To a solution of 5-bromo-2-(difluoromethyl)pyridine (400 mg, 1.92 mmol)in THF (2 mL) at 0° C. was added isopropylmagnesium chloride-lithiumchloride complex (1.3 M, 2.96 mL) dropwise. The reaction was allowed tostir at room temperature for 2 hours, then DMF (703 mg, 9.62 mmol) wasadded at 0° C. and the reaction was stirred for an additional 12 hoursat room temperature. The reaction was quenched with 2M HCl (aq) andbasified with 1M NaOH (aq) until pH=7. The organic layer was separatedand the aqueous layer was extracted with dichloromethane. The combinedorganic layers were dried over Na₂SO₄ and concentrated.

The residue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 10:1) to give6-(difluoromethyl)nicotinaldehyde (130 mg).

Preparation of methyl 5-methoxypyrazine-2-carboxylate

To a solution of 5-methoxypyrazine-2-carboxylic acid (1 g, 6.49 mmol) inMeOH (20 mL) was added SOCl₂ (927 mg, 7.79 mmol) at 15° C. The mixturewas refluxed at 60° C. for 2 hours to give a brown solution. Thereaction mixture was concentrated under reduced pressure to give aresidue. The residue was diluted with dichloromethane (20 mL) and the pHwas adjusted to 8 by NaHCO₃ (aq, 50 mL). The mixture was extracted withdichloromethane (100 mL×3). The combined organic layers were washed withbrine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give methyl 5-methoxypyrazine-2-carboxylate(1.02 g).

Preparation of (5-methoxypyrazin-2-yl)methanol

To a solution of methyl 5-methoxypyrazine-2-carboxylate (200 mg, 1.19mmol) in THF (0.1 mL) and MeOH (4 mL) was added NaBH₄ (225 mg, 5.95mmol). The mixture was stirred at 15° C. for 16 hours. The mixture wasquenched with water (5 mL), then diluted with further water (15 mL),extracted with ethyl acetate (2×25 mL) then 20 percent 2-propanol indichloromethane (25 mL). The combined organic extracts were dried overanhydrous Na₂SO₄, filtered and concentrated to give(5-methoxypyrazin-2-yl)methanol (122 mg).

Preparation of 5-methoxypyrazine-2-carbaldehyde

To a solution of (5-methoxypyrazin-2-yl)methanol (115 mg, 0.82 mmol) indichloromethane (3 mL) was added MnO₂ (714 mg, 8.21 mmol) at 15° C. Thereaction mixture was refluxed at 50° C. for 18 hours. The reactionmixture was cooled to 20° C., filtered through celite and washed withdichloromethane (100 ml). The filtrate was concentrated to afford5-methoxypyrazine-2-carbaldehyde (45 mg).

Preparation of 4-ethyloxazolidin-2-one

To a solution of 2-aminobutan-1-ol (1 g, 11.2 mmol), carbonyldiimidazole (2.18 g, 13.5 mmol) in THF (3 mL) was added Et₃N (1.14 g,11.2 mmol) under argon atmosphere. The reaction was stirred at roomtemperature for 12 h. The mixture was concentrated and the residue waspurified by column chromatography (SiO₂, Petroleum ether: Ethylacetate=10:1 to 5:1) to give 4-ethyloxazolidin-2-one (800 mg).

Preparation of5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde

A solution of i-PrMgCl—LiCl (1.3 M, 3.6 mL) in THF was dropwise addedinto a mixture of5,7-dibromo-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine (1.3 g, 3.9mmol) in THF (25 mL) at 0° C. The mixture was stirred at roomtemperature for 30 min. Then the mixture was recooled to 0° C. and DMF(1.4 g, 19.5 mmol, 1.5 mL) was added and the resulting mixture wasstirred at room temperature for another 2.5 hours. NH₄Cl (aq. 2 mL) wasadded to quench the reaction, then water (20 mL) was added and themixture was extracted with ethyl acetate (20 mL×3). The combined organiclayer was washed with brine (10 mL), dried over Na₂SO₄ and concentrated.The crude mixture was purified by flash chromatography with petroleumether:ethyl acetate=30:1-20:1 to give5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde(800 mg).

Preparation ofN-((5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)methyl)-5-methoxypyridin-3-amine

To a solution of5-bromo-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine-7-carbaldehyde (50mg, 0.18 mmol) in dioxane (3 mL) was added Ti(i-PrO)₄ (101 mg, 0.35mmol) and 5-methoxypyridin-3-amine (44 mg, 0.35 mmol). The mixture wasstirred at 80° C. for 14 hours. After the reaction mixture had cooled toroom temperature, EtOH (3 mL) was added followed by addition of NaBH₄(35 mg, 0.9 mmol). The mixture was stirred at room temperature for 15minutes. Water (0.5 mL) was added to quench the reaction at 0° C. Andthe resulting mixture was stirred at room temperature for 10 minutes,then filtered and the residue was washed with ethyl acetate (30 mL×3).The combined organic layers was dried and concentrated. The crudeproductN-[(5-bromo-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl)methyl]-5-methoxy-pyridin-3-amine(69 mg) was used into the next step without further purification.

N-((5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)methyl)-1-methyl-1H-1,2,4-triazol-3-aminewas prepared in similar manner from5-bromo-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine-7-carbaldehyde and1-methyl-1,2,4-triazol-3-amine.

Preparation of5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde

A mixture of5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde(0.56 g, 1.98 mmol), (2-ethoxy-3-pyridyl)boronic acid (497 mg, 2.98mmol), Pd(dppf)Cl₂ (145 mg, 0.2 mmol), Cs₂CO₃ (1.94 g, 5.95 mmol) indioxane (8 mL), water (2 mL) was stirred at 100° C. for 2 hours. Themixture was concentrated under reduced pressure. The residue wasextracted with ethyl acetate (30 mL×2). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=10:1 to 3:1)to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde(0.55 g).

Preparation of5-(2-ethoxypyridin-3-yl)-7-ethynyl-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine

A mixture of5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde(0.55 g, 1.70 mmol), 1-diazo-1-dimethoxyphosphoryl-propan-2-one (423 mg,2.20 mmol) and Cs₂CO₃ (1.66 g, 5.09 mmol) in MeOH (7 mL) was stirred atroom temperature for 2 hours. The mixture was concentrated under reducedpressure and extracted with DCM (20 mL×2). The combined organic layerswere washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give crude.5-(2-ethoxypyridin-3-yl)-7-ethynyl-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine(0.5 g).

Preparation of tert-butyl((6-chloropyrazin-2-yl)methyl)carbamate

To a suspension of Raney-Ni (307 mg, 3.59 mmol) in EtOH (20 mL) wasadded 6-chloropyrazine-2-carbonitrile (1.00 g, 7.17 mmol) andtert-butoxycarbonyl tert-butyl carbonate (1.72 g, 7.88 mmol), then thereaction mixture was stirred at room temperature under H₂ (45 psi) for16 hours. The reaction mixture was filtered through celite and thefiltrate was concentrated under reduced pressure to give a residue. Theresidue was purified by flash silica gel chromatography (eluention with0-10% Ethyl acetate/Petroleum ether gradient) to give tert-butylN-[(6-chloropyrazin-2-yl)methyl]carbamate (1.05 g).

Preparation of tert-butyl ((6-methoxypyrazin-2-yl)methyl)carbamate

To an ice cold solution of tert-butylN-[(6-chloropyrazin-2-yl)methyl]carbamate (500 mg, 2.05 mmol) in MeOH(10 mL) was added sodium methoxide (443 mg, 8.21 mmol), then thereaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was concentrated under reduced pressure. The residuewas diluted with water (100 mL) and extracted with ethyl acetate (100mL×3). The combined organic layers were washed with saturated aqueousNH₄Cl (100 mL×2), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified byflash silica gel chromatography (eluention with 0-16% Ethylacetate/Petroleum ether) to give tert-butylN-[(6-methoxypyrazin-2-yl)methyl]carbamate (300 mg).

Preparation of (6-methoxypyrazin-2-yl)methanamine hydrochloride

A solution of tert-butyl N-[(6-methoxypyrazin-2-yl)methyl]carbamate (350mg, 1.46 mmol) in 4N HCl/dioxane (10 mL) was stirred at room temperaturefor 2 hours. The reaction mixture was concentrated under pressure togive a (6-methoxypyrazin-2-yl)methanamine hydrochloride. The crudeproduct was used directly without further purification.

The following compound was prepared in a similar manner

(3-methoxypyrazin-2-yl)methanamine hydrochloride Preparation of(4-methoxy-3-pyridyl)methanamine

To a solution of 4-methoxypyridine-3-carbonitrile (200 mg, 1.49 mmol),25% ammonia in water (0.23 mL) and MeOH (5 mL) was added to Raney-Ni (30mg, 10%), the reaction mixture was stirred at room temperature for 4hours under a H₂ atmosphere (45 psi). The reaction mixture was filteredto remove the catalyst and the filter cake was washed with MeOH (10mL×3), the filtrate was concentrated under vacuo to give the crudeproduct (4-methoxy-3-pyridyl)methanamine (150 mg).

Preparation of 6-methylheptyl3-((5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thio)propanoate

A solution of5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine (150 mg,0.45 mmol), 6-methylheptyl 3-mercaptopropanoate (124 mg, 0.57 mmol),DIPEA (116 mg, 157 μL 0.90 mmol) in NMP (2 mL) was stirred at rt underinert atmosphere over 15 minutes after which it was inserted in an oilbath at 50° C. and stirred overnight. Partitioned between water (25 mL)and a solution of pentane:ethyl acetate (1:1) (50 mL). The aq. layer wasextracted with fresh pentane:ethyl acetate (1:1) (20 mL). The combinedorg. layers were dried (Na₂SO₄) and concentrated. The crude material waspurified by flash chromatography with heptane:ethyl acetate 1:0 to 0:1to give 6-methylheptyl3-((5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thio)propanoate(194 mg).

Preparation of 6-methylheptyl3-((5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thio)propanoate

A suspension of 6-methylheptyl3-((5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thio)propanoate(194 mg, 0.41 mmol),2-ethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (123mg, 0.50 mmol), PdCl₂(dppf)-CH₂C2 (84 mg, 0.10 mmol), K₂CO₃ (85 mg, 0.62mmol) in 1,4-dioxane (5.5 mL) and water (0.3 mL) was degassed bybubbling nitrogen over 3 minutes and then stirred at 105° C. over 4hours. Most of the solvent was removed under vacuo. The obtained residuewas taken in ethyl acetate (25 mL) and filtered through a short pad ofCelite which was rinsed with ethyl acetate (10 mL×2). The combinedfiltrates were washed with brine (20 mL), dried (Na₂SO₄) andconcentrated. The crude material was purified by flash chromatographywith heptane:ethyl acetate 1:0 to 0:1 to give 6-methylheptyl3-((5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thio)propanoate(128 mg).

Preparation of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate

To a solution of prop-2-yn-1-ol (500 mg, 0.52 ml, 8.92 mmol) and ethyl2-nitroacetate (2.26 g, 1.88 ml, 16.95 mmol) in EtOH (15 ml) was addedDABCO (1.0 g, 8.92 mmol). The mixture was stirred at 80° C. for 72 hoursunder microwave irradiation. The mixture was concentrated and purifieddirectly by flash chromatography with heptane:ethyl acetate=1:0 to 0:1to give ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (400 mg).

Preparation of ethyl 5-(fluoromethyl)isoxazole-3-carboxylate

To a solution of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (50.0mg, 0.29 mmol) in DCM (2 mL) was added diethylaminosulfur trifluoride(70.6 mg, 0.06 ml, 0.44 mmol). The mixture was stirred at 40° C. for 1hour. Water (3 mL) was added and the mixture was extracted with ethylacetate (5 mL×3). The combined organic layers were washed with brine (5mL), dried over Na₂SO₄ and concentrated. The crude mixture was purifiedby flash chromatography with heptane:ethyl acetate=1:0 to 0:1 to giveethyl 5-(fluoromethyl)isoxazole-3-carboxylate (41.0 mg).

Preparation of (5-(fluoromethyl)isoxazol-3-yl)methanol

To a solution of ethyl 5-(fluoromethyl)isoxazole-3-carboxylate (50.0 mg,0.29 mmol) in THF (4 mL) at 0° C. was added lithium aluminum hydride(0.43 mL, 0.43 mmol, 1 M in THF). The mixture was stirred at 0° C. for 1hour. A half saturated solution of sodium potassium tartarate (5 mL) wasadded and the mixture was stirred vigorously for 30 minutes. The mixturewas then extracted with ethyl acetate (10 mL×3). The combined organiclayers were washed with brine (10 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by flash chromatographywith heptane:ethyl acetate=1:0 to 0:1 to give(5-(fluoromethyl)isoxazol-3-yl)methanol (29.0 mg).

Preparation of 3-(bromomethyl)-5-(fluoromethyl)isoxazole

To a solution of (5-(fluoromethyl)isoxazol-3-yl)methanol (17.0 mg 0.13mmol) in MeCN (2 mL) was added triphenylphosphine (68 mg, 0.26 mmol),2,6-lutidine (13.9 mg, 0.015 mL, 0.13 mmol) and CBr₄ (86 mg, 0.26 mmol).The reaction mixture was stirred at room temperature for 1 hour. Themixture was concentrated purified directly by flash chromatography withheptane:ethyl acetate=1:0 to 0:1 to give3-(bromomethyl)-5-(fluoromethyl)isoxazole (12 mg).

Preparation of ethyl 5-(bromomethyl)isoxazole-3-carboxylate

To a solution of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (50 mg,0.29 mmol) in MeCN (2 mL) was added triphenylphosphine (153 mg, 0.58mmol), 2,6-lutidine (31.3 mg, 0.034 mL, 0.29 mmol) and CBr₄ (194 mg,0.58 mmol). The reaction mixture was stirred at room temperature for 1.5hours. The mixture is concentrated and purified directly by flashchromatography with heptane:ethyl acetate=1:0 to 0:1 to give ethyl5-(bromomethyl)isoxazole-3-carboxylate (68 mg).

Preparation of (5-(bromomethyl)isoxazol-3-yl)methanol

To a solution of ethyl 5-(bromomethyl)isoxazole-3-carboxylate (26 mg,0.11 mmol) in THF (1 mL) at 0° C. was added diisopropyl aluminiumhydride (0.12 ml, 0.12 mmol, 1 M in THF). The mixture was stirred at 0°C. for 2 hours. Another 0.12 mmol of diisopropyl aluminium hydridesolution was added and the mixture was stirred for another hour. 3 dropsof 4M HCl (aq) was added followed by a half saturated solution of sodiumpotassium tartarate (5 mL). The mixture was stirred vigorously for 30minutes. The mixture was then extracted with ethyl acetate (10 mL×3).The combined organic layers were washed with brine (10 mL), dried overNa₂SO₄ and concentrated to give (5-(bromomethyl)isoxazol-3-yl)methanol(21.3 mg, 0.11 mmol).

Preparation of 5-(bromomethyl)-3-(fluoromethyl)isoxazole

To a solution of (5-(bromomethyl)isoxazol-3-yl)methanol in DCM (1 mL)was added diethylaminosulfur trifluoride (70.6 mg, 0.06 ml, 0.44 mmol).The mixture was stirred at 40° C. for 1 hour. Water (3 mL) was added andthe mixture was extracted with ethyl acetate (5 mL×3). The combinedorganic layers were washed with brine (5 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by flash chromatographywith heptane:ethyl acetate=1:0 to 0:1 to give5-(bromomethyl)-3-(fluoromethyl)isoxazole (7.0 mg, 0.04 mmol).

Preparation of methyl 1-(difluoromethyl)-1H-pyrazole-4-carboxylate

To a solution of 1-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (100mg, 0.62 mmol) in DCM (4 mL) was added (diazomethyl)trimethylsilane(0.62 mL, 1.23 mmol, 2 M in hexane). The mixture was stirred at roomtemperature for 2 hours. Acetic acid (0.2 mL) was added and the mixturewas co-evaporated with toluene (2×20 mL) to give methyl1-(difluoromethyl)-1H-pyrazole-4-carboxylate (99.0 mg, 0.56 mmol).

Preparation of (1-(difluoromethyl)-1H-pyrazol-4-yl)methanol

To a solution of methyl 1-(difluoromethyl)-1H-pyrazole-4-carboxylate(120 mg, 0.68 mmol) in THF (4 mL) at 0° C. was added lithium aluminumhydride (1.0 mL, 1.0 mmol, 1 M in THF). The mixture was stirred at 0° C.for 1 hour. A half saturated solution of sodium potassium tartarate (5mL) was added and the mixture was stirred vigorously for 30 minutes. Themixture was then extracted with ethyl acetate (10 mL×3). The combinedorganic layers were washed with brine (10 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by flash chromatographywith heptane:ethyl acetate=1:0 to 0:1 to give(1-(difluoromethyl)-1H-pyrazol-4-yl)methanol (101 mg, 0.68 mmol).

Preparation of 4-(bromomethyl)-1-(difluoromethyl)-1H-pyrazole

To a solution of (1-(difluoromethyl)-1H-pyrazol-4-yl)methanol (30 mg,0.20 mmol) in MeCN (1.5 mL) was added triphenylphosphine (106 mg, 0.41mmol), 2,6-lutidine (21.7 mg, 23.6 μl, 0.20 mmol) and CBr₄ (134 mg, 0.41mmol). The reaction mixture was stirred at room temperature for 1 hour.The mixture is concentrated and purified directly by flashchromatography with heptane:ethyl acetate=1:0 to 0:1 to give4-(bromomethyl)-1-(difluoromethyl)-1H-pyrazole (29 mg).

Preparation ofN-((1-(difluoromethyl)-1H-pyrazol-4-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

To a suspension of NaH (3.79 mg, 0.095 mmol, 60% w/w) in THF (1 mL) at0° C. was added5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(20.5 mg, 0.05 mmol). The mixture was stirred at 0° C. for 15 minutesbefore 4-(bromomethyl)-1-(difluoromethyl)-1H-pyrazole (10 mg, 0.05 mmol)in THF (1 mL) was added. The reaction mixture was slowly allowed toreach room temperature and stirred for 2 hours. Water (5 mL) was addedand the mixture was extracted with ethyl acetate (5 mL×3). The combinedorganic layers were washed with brine (10 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by flash chromatographywith heptane:ethyl acetate=1:0 to 0:1 to giveN-((1-(difluoromethyl)-1H-pyrazol-4-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(23 mg, 0.04 mmol).

The following examples were prepared in a similar manner

5-(2-ethoxypyridin-3-yl)-N-((5-(fluoromethyl)isoxazol-3-yl)methyl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 3-(bromomethyl)-5-(fluoromethyl)isoxazole.

5-(2-ethoxypyridin-3-yl)-N-((3-(fluoromethyl)isoxazol-5-yl)methyl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-(bromomethyl)-3-(fluoromethyl)isoxazole.

Preparation of (2-oxo-1,2-dihydropyridin-3-yl)boronic acid

To a solution of 3-bromopyridin-2(1H)-one (3.3 g, 19 mmol) in THF (200mL) cooled to −78° C., TMEDA (tetramethylethylenediamine) (6.6 g, 57mmol) was added dropwise over 15 minutes followed by addition of n-BuLi(in hexane, 2.5 M, 23 mL). The resulting mixture was stirred for 15 minat −78° C. and then warmed to room temperature. The reaction mixture wascooled to 0° C., and trimethyl borate (3.9 g, 38 mmol) was addeddropwise over 30 minutes. After the addition was complete, the reactionmixture was warmed to room temperature and was stirred for 15 hours. Themixture was then cooled to 0° C. and a small amount of ice was addedfollowed by HCl (aq. 100 mL, 2M). The THF was removed under reducedpressure, and the aqueous solution was washed twice with dichloromethane(50 mL×2). Concentrated aqueous NaOH was added slowly until pH=5 wasattained and a precipitate formed. The mixture was cooled to 0° C. andstirred for 10 minutes. The solid was collected by filtration, washedwith cold water, and dried under vacuum to afford(2-oxo-1,2-dihydropyridin-3-yl)boronic acid.

Preparation of 2-(trifluoromethyl)pyridine-3-carbonitrile

To 3-bromo-2-(trifluoromethyl)pyridine (1 g, 4.42 mmol) in NMP (10 mL)was added Zn(CN)₂ (572 mg, 4.87 mmol) and Pd(PPh₃)₄ (1 g, 0.885 mmol),then the reaction mixture was stirred at 140° C. for 1 hour by microwaveheating. The reaction mixture was cooled to room temperature, filteredthrough celite and washed with ethyl acetate (100 mL). The reactionmixture was extracted with ethyl acetate (100 mL×2) and the organiclayers were washed with water (100×3 mL), brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by flash chromatography onsilica gel (petroleum ether/ethyl acetate) to give 2-(trifluoromethyl)pyridine-3-carbonitrile.

Preparation of (2-(trifluoromethyl) pyridin-3-yl)methanamine

To a solution of Raney-Ni (50 mg, 0.581 mmol) in MeOH (20 mL) was added2-(trifluoromethyl)pyridine-3-carbonitrile (500 mg, 2.91 mmol) andNH₃.water (6 M, 5 mL), then the reaction mixture was stirred at 30° C.for 2 hours. The reaction mixture was concentrated under reducedpressure to give a residue. To the residue was added HCl (2M, 2 mL) andwater (10 mL). The resulting solution was lyophilized. The crude productwas used for next step without further purification.

Preparation of tert-butyl ((5-methoxypyrimidin-2-yl)methyl)carbamate

A mixture of 5-methoxypyrimidine-2-carbonitrile (100 mg, 0.74 mmol) andBoc₂O (194 mg, 0.89 mmol) and MeOH (5 mL) was added to Raney-Ni (30 mg,10%), the reaction mixture was stirred at room temperature for 2 hoursunder a H₂ atmosphere (45 psi). The reaction mixture was filtered toremove the catalyst and the filter cake was washed with MeOH (10 mL×3),and the filtrate was concentrated under vacuum. The crude product waspurified by flash chromatography on silica gel (0-10% ethyl acetate inpetroleum ether) to givetert-butyl((5-methoxypyrimidin-2-yl)methyl)carbamate.

Preparation of (5-methoxypyrimidin-2-yl)methanamine hydrochloride

A mixture of tert-butyl ((5-methoxypyrimidin-2-yl)methyl)carbamate (100mg, 0.42 mmol) and dichloromethane (5 mL) and HCl/dioxane (4 M, 2 mL)was stirred at room temperature for 0.5 hour. Water (10 mL) was added tothe reaction mixture and the solution was concentrated under vacuum toremove the organic phase and the aqueous phase was lyophilized to givethe crude product. The crude product(5-methoxypyrimidin-2-yl)methanamine was obtained.

Preparation of 4-methoxypyrimidine-2-carbonitrile

2-chloro-4-methoxy-pyrimidine (600 mg, 4.15 mmol) and Zn(CN)₂ (292 mg,2.49 mmol) and Pd(dppf)Cl₂ (607 mg, 0.83 mmol) were taken up into amicrowave tube in NMP (3 mL). The sealed tube was heated at 140° C. for1 hour under microwave irradiation. The reaction mixture was cooled toroom temperature, filtered through celite and washed with ethyl acetate(20 mL). The reaction mixture was extracted with ethyl acetate (20 mL×3)and the organic layers were washed with water (20×3 mL), brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate) to give4-methoxypyrimidine-2-carbonitrile.

Preparation of tert-butyl N-[(4-methoxypyrimidin-2-yl)methyl]carbamate

To a solution of Raney-Ni (25 mg, 0.296 mmol) in EtOH (5 mL) was added4-methoxypyrimidine-2-carbonitrile (200 mg, 1.48 mmol) and Boc₂O (355mg, 1.63 mmol, 0.374 mL) under N₂, then the reaction mixture was stirredat room temperature under H₂ (45 psi) for 2 hours. The reaction mixturewas filtered through celite and concentrated under reduced pressure togive a residue. The residue was purified by flash chromatography onsilica gel (petroleum ether/ethyl acetate) to give tert-butylN-[(4-methoxypyrimidin-2-yl)methyl]carbamate.

Preparation of (4-methoxypyrimidin-2-yl)methanamine hydrobromide

A solution of tert-butyl N-[(4-methoxypyrimidin-2-yl)methyl]carbamate(100 mg, 0.418 mmol) in HBr/water (3 mL) was stirred at room temperaturefor 1 hour. The reaction mixture was concentrated under reduced pressureto give a residue. The crude product was used in the next step withoutfurther purification.

Preparation of 6-methoxypyrimidine-4-carbonitrile

To a solution of 4-chloro-6-methoxy-pyrimidine (1 g, 6.92 mmol) in DMF(10 mL) was added Pd(PPh₃)₄ (2 g, 1.38 mmol) and Zn(CN)₂ (487 mg, 4.15mmol). The reaction mixture was stirred at 80° C. for 16 hours. Thereaction mixture was cooled to room temperature, filtered through celiteand washed with dichloromethane (100 mL). The reaction mixture wasextracted with dichloromethane (100 mL×3) and the organic layers werewashed with water (100×3 mL) and brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by flash chromatography on silica gel(petroleum ether/ethyl acetate) to give6-methoxypyrimidine-4-carbonitrile.

Preparation of tert-butyl N-((6-methoxypyrimidin-4-yl)methyl)carbamate

To a solution of Raney-Ni (25 mg, 0.296 mmol) in EtOH (5 mL) was added6-methoxypyrimidine-4-carbonitrile (200 mg, 1.48 mmol) and Boc₂ (355 mg,1.63 mmol, 0.374 mL), then the reaction mixture was stirred at roomtemperature under H₂ (45 psi) for 2 hours. The reaction mixture wasfiltered through celite and washed with EtOH (20 mL×2), the filtratedwas concentrated under reduced pressure to give a residue. The residuewas purified by flash chromatography on silica gel (petroleumether/ethyl acetate) to give tert-butylN-[(6-methoxypyrimidin-4-yl)methyl]carbamate.

Preparation of (6-methoxypyrimidin-4-yl)methanamine

A solution of tert-butyl N-[(6-methoxypyrimidin-4-yl)methyl]carbamate(240 mg, 1.00 mmol) in HCl/dioxane (10 mL) was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated underreduced pressure to give a residue. The residue was used in the nextstep without further purification.

Preparation of 3-bromopicolinaldehyde

To a solution of 2,3-dibromopyridine (5 g, 21.11 mmol) in toluene (50mL), t-BuLi (1.3 M, 19.50 mL) was dropwise added at −78° C. under N₂.The resulting mixture was stirred at −78° C. for 2 hours. DMF (1.9 g,25.33 mmol) was added dropwise at −78° C. The mixture was stirred at−78° C. for another 2 hours. The solution was quenched with NH₄Cl (aq. 1mL) at −78° C., and the mixture was concentrated under vacuum. Theresidue was purified by column chromatography on silica gel (Petroleumether/ethyl acetate=10/1 to 1/1) to afford 3-bromopicolinaldehyde.

Preparation of 3-bromo-2-(difluoromethyl)pyridine

To a solution of 3-bromopicolinaldehyde (1.3 g, 6.99 mmol) indichloromethane (30 mL) was added diethylaminosulfur trifluoride (2.25g, 13.98 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2hours under N₂. The solution was quenched with NaHCO₃ (aq. 15 mL) at 0°C. The aqueous phase was extracted with dichloromethane (10 mL×3). Thecombined organic phases were washed with brine (15 mL×1), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (petroleum ether/ethylacetate=1/0, 10/1) to afford 3-bromo-2-(difluoromethyl)pyridine

Preparation of 2-(difluoromethyl)nicotinonitrile

To a mixture of 3-bromo-2-(difluoromethyl)pyridine (600 mg, 2.88 mmol)and Zn(CN)₂ (373 mg, 3.17 mmol) in NMP (10 mL) was added Pd(PPh₃)₄ (333mg, 0.29 mmol). The reaction mixture was heated by microwave irradiationat 140° C. for 1 hour. The reaction mixture was poured into ethylacetate (50 mL). The mixture was washed with water (20 mL×3) and brine(15 mL×1), dried over Na₂SO₄ and filtered. The filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=1/0, 2/1) to afford2-(difluoromethyl)nicotinonitrile.

Preparation oftert-butyl((2-(difluoromethyl)pyridin-3-yl)methyl)carbamate

A mixture of 2-(difluoromethyl)nicotinonitrile (0.4 g, 2.60 mmol),(Boc)₂O (680 mg, 3.11 mmol) and Raney-Ni (22 mg, 0.26 mmol) in MeOH (20mL) was stirred at 30° C. for 2 hours under H₂ (40 psi). The mixture wasfiltered and the filtrate was concentrated under vacuum. The residue waspurified by silica gel chromatography (petroleum ether/ethylacetate=1/0, 3/1) to afford tert-butyl((2-(difluoromethyl)pyridin-3-yl)methyl)carbamate.

Preparation of (2-(difluoromethyl)pyridin-3-yl)methanamine hydrochloride

To a solution of tert-butyl((2-(difluoromethyl)pyridin-3-yl)methyl)carbamate (0.6 g, 2.32 mmol) indichloromethane (5 mL) was added HCl/dioxane (4M, 1 mL) at 0° C. Thereaction mixture was stirred at room temperature for 12 hours. Themixture was concentrated under vacuum to afford(2-(difluoromethyl)pyridin-3-ylmethanamine hydrochloride.

Preparation of 3-bromo-2-ethoxypyridine

To a mixture of 3-bromo-2-chloropyridine (200 mg, 1 mmol) in EtOH (5 mL)was added t-BuOK (233 mg, 2 mmol). The mixture was stirred at 80° C. for12 hours. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give the crude product. The residue waspurified by flash chromatography on silica gel (0%-40% ethyl acetate inpetroleum ether) to afford 3-bromo-2-ethoxypyridine.

Preparation of 2-ethoxynicotinonitrile

To a solution of 3-bromo-2-ethoxy-pyridine (350 mg, 1.7 mmol) in NMP (2mL) was added Zn(CN)₂ (244 mg, 2.1 mmol) and Pd(dppf)Cl₂ (127 mg, 0.17mmol). The mixture was degassed with N₂ and heated at 140° C. undermicrowave irradiation for 1 hour. The mixture was cooled to roomtemperature and filtered through celite. The filtered cake was washedwith ethyl acetate (30 mL). The filtrate was washed with water (20 mL×2)and brine (20 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on silica gel (0%-20% ethylacetate in petroleum ether) to give 2-ethoxynicotinonitrile.

Preparation of tert-butyl ((2-ethoxypyridin-3-yl)methyl)carbamate

To a solution of Raney-Ni (24 mg, 0.28 mmol) in EtOH (5 mL) was added2-ethoxynicotinonitrile (210 mg, 1.4 mmol) and Boc₂O (371 mg, 1.7 mmol).The reaction mixture was stirred at room temperature under H₂ (45 psi)for 2 hours. The reaction mixture was filtered through celite and washedwith EtOH (20 mL×2), then the filtrate was concentrated under reducedpressure to give a residue. The residue was purified by preparative HPLCto afford tert-butyl ((2-ethoxypyridin-3-yl)methyl)carbamate.

Preparation of (2-ethoxypyridin-3-yl)methanamine

A solution of tert-butyl ((2-ethoxypyridin-3-yl)methyl)carbamate (85 mg,0.34 mmol) in HCl/dioxane (4 M, 2 mL) was stirred at room temperaturefor 12 hours. The reaction mixture was concentrated under reducedpressure to afford 2-ethoxypyridin-3-yl)methanamine.

Preparation of 3-methoxypyridine-4-carbonitrile

3-chloropyridine-4-carbonitrile (250 mg, 1.80 mmol) was dissolved in DMF(5 mL) and cooled to ice bath temperature. CH₃ONa (194.95 mg, 3.61 mmol)was added slowly and the reaction mixture was stirred at roomtemperature for 2 hours under a N₂ atmosphere. Water (20 mL) and ethylacetate (20 mL) were added to the reaction mixture. The aqueous phasewas extracted with ethyl acetate (20 mL×2). The organic phases werecombined and dried over anhydrous Na₂SO₄ (5 g), filtered andconcentrated under vacuum to give the product3-methoxypyridine-4-carbonitrile.

Preparation of (3-methoxy-4-pyridyl)methanamine

A mixture of 3-methoxypyridine-4-carbonitrile (200 mg, 1.49 mmol), NH₃in water (314 mg, 2.24 mmol, 25%) and Raney-Ni (30 mg) in MeOH (5 mL)was stirred at room temperature for 3 hours under a H₂ atmosphere (45psi). The reaction mixture was filtered to remove the catalyst and thefilter cake was washed with MeOH (10 mL×3). The filtrate wasconcentrated under vacuum. The residue was dissolved in 1 M HCl (30 mL)and the solution was lyophilized to give(3-methoxy-4-pyridyl)methanamine hydrochloride (296 mg). A mixture of(3-methoxy-4-pyridyl)methanamine hydrochloride (100 mg, 0.57 mmol),Ambersep 900(OH) and iron exchange resin (150 mg) in MeCN (5 mL) wasstirred at room temperature for 0.5 hour. Universal indicator papershowed that pH of the solution was 9-10.

The reaction mixture was filtered to remove the resin and the filtratewas dried over anhydrous Na₂SO₄, filtered and concentrated under vacuumto give (3-methoxy-4-pyridyl)methanamine.

Preparation of methyl 4-methoxypyrimidine-5-carboxylate

To a solution of 5-bromo-4-methoxypyrimidine (1 g, 5.29 mmol) in MeOH(20 mL) was added triethylamine (1.07 g, 10.58 mmol) and Pd(dppf)Cl₂(774 mg, 1.06 mmol). The suspension was degassed and purged with COseveral times. The mixture was heated at 80° C. under CO (50 psi) for 16hours. The mixture was filtered through celite and the filtrate wasconcentrated. The residue was purified by flash chromatography on silicagel (petroleum ether/ethyl acetate) to give methyl4-methoxypyrimidine-5-carboxylate.

Preparation of (4-methoxypyrimidin-5-ylmethanol

To a solution of methyl 4-methoxypyrimidine-5-carboxylate (250 mg, 1.49mmol) in THF (5 mL) was added LiAlH₄ (169 mg, 4.46 mmol) at −40° C. Themixture was stirred at −40° C. for 0.5 hour. Water (0.5 mL) and 15% NaOH(0.5 mL) were added. The mixture was extracted with ethyl acetate (20mL×2). The combined organic layer was washed with water (10 mL), driedover Na₂SO₄, filtered and concentrated. The residue was purified byflash chromatography on silica gel (petroleum ether/ethyl acetate) togive (4-methoxypyrimidin-5-yl)methanol.

Preparation of 5-(bromomethyl)-4-methoxypyrimidine

To a solution of (4-methoxypyrimidin-5-yl)methanol (50 mg, 0.36 mmol) indry dichloromethane (2 mL) was added PBr₃ (144 mg, 0.53 mmol) at 0° C.The mixture was stirred at 0° C. for 0.5 hour. The mixture wasconcentrated and ice-water (5 g) was added.

The aqueous layer was extracted with ethyl acetate (20 mL×2). Theorganic layer was dried over Na₂SO₄, filtered and concentrated to give5-(bromomethyl)-4-methoxypyrimidine (70 mg, crude).

Preparation of 3-bromo-2-(ethoxy-d₅)pyridine

NaH (60% dispersion in oil) (227 mg, 5.68 mmol) was suspended in THF (13ml) and cooled to ice bath temperature. A solution of ethanol-de (296mg, 5.68 mmol) in THF (1.2 ml) was added dropwise. The resultingsuspension was stirred at ice bath temperature over 10 minutes afterwhich the cooling bath was removed and stirring continued for 0.5 hour.The resulting mixture was recooled to ice bath temperature and asolution of 3-bromo-2-fluoropyridine (500 mg, 2.84 mmol) in THF (1.2 ml)was added dropwise. After stirring for 15 minutes at ice bathtemperature the cooling was removed and stirring continued for 45minutes further at room temperature after which a reflux condenser wasinserted and the mixture was heated to 65° C. for 10 hours. The mixturewas recooled to ice bath temperature and quenched with a few drops ofwater. Most of the solvent was removed under vacuo. The obtained residuewas partioned between ethyl acetate (25 ml) and brine (10 ml). Theorganic layer was dried (Na₂SO₄) and concentrated. The residue waspurified by flash chromatography on silica gel (heptane/ethyl acetate)to give 3-bromo-2-(ethoxy-d)pyridine.

The following compounds were prepared in a similar manner:

3-bromo-2-(ethoxy-2,2,2-d₃)pyridine prepared from3-bromo-2-fluoropyridine and ethanol-2,2,2-d₃.

3-bromo-2-(ethoxy-1,1-d₂)pyridine prepared from 3-bromo-2-fluoropyridineand ethanol(1,1-d₂).

Preparation of2-(ethoxy-d₅)-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2yl)pyridine

A suspension of 3-bromo-2-(ethoxy-d₅)pyridine (152 mg, 0.73 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (242 mg,0.95 mmol), PdCl₂(dppf)-CH₂Cl₂ (120 mg, 0.15 mmol) and KOAc (216 mg,2.20 mmol) in 1,4-dioxane (2.5 m) was degassed by bubbling N₂ throughthe suspension for approx. 3 minutes after which it was heated to 110°C. for 4.5 hours. The resulting suspension was diluted with ethylacetate (10 ml) and filtered through a short pad of Celite which wasrinsed with ethyl acetate (2×10 ml). Most of the solvent was removedunder vacuo. The obtained residue was taken into ethyl acetate (50 ml)and washed with brine (30 m). The organic layer was dried (Na₂SO₄),filtered and concentrated. Purification by flash chromatography onsilica gel (elution from heptane to ethyl acetate) delivered2-(ethoxy-d₅)-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2yl)pyridine.

The following compounds were prepared in a similar manner:

2-(Ethoxy-2,2,2-d₃)-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2yl)pyridineprepared from 3-bromo-2-(ethoxy-2,2,2-d₃)pyridine.

2-(Ethoxy-1,1-d₂)-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2yl)pyridineprepared from 3-bromo-2-(ethoxy-1,1-d₂)pyridine.

Preparation of 2′-ethoxy-6-methyl-[2,3′-bipyridin]-5-amine

N₂ was bubbled through a mixture of 6-bromo-2-methylpyridin-3-amine (2.5g, 13.4 mmol),2-ethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5.0 g,20.1 mmol), PdCl₂(dppf)-CH₂C2 (2.18 g, 2.67 mmol) and potassiumcarbonate (3.69 g, 26.7 mmol) in 1,4-dioxane (126 ml) and water (12 ml)for 10 minutes. A reflux condenser was inserted and the reaction mixturewas heated at 105° C. for 2.5 hours under an inert atmosphere afterwhich most of the solvent was removed under vacuo. The obtained residuewas taken into ethyl acetate (150 ml) and filtered through a short padof Celite which was rinsed with ethyl acetate (2×50 ml). Concentrationand purification by flash chromatography on silica gel (elution withheptane to heptane/dichloromethane (1:1) toheptane/dichloromethane/ethyl acetate (1:1:1.5)) delivered2′-ethoxy-6-methyl-[2,3′-bipyridin]-5-amine.

Preparation of 4-chloro-2′-ethoxy-6-methyl-[2,3′-bipyridin]-5-amine

A solution of 2′-ethoxy-6-methyl-[2,3′-bipyridin]-5-amine (7.40 g, 22.6mmol) and N-chloro succinimide (3.77 g, 28.2 mmol) in NMP (104 ml) wasstirred at room temperature for 15 minutes under an inert atmosphere. Areflux condenser was inserted and the solution was heated to 80° C. for3.5 hours after which it was allowed to reach room temperature andpartitioned between ethyl acetate (300 ml) and aqueous saturated NaHCO₃(3×200 ml). The combined aqueous layers were extracted with ethylacetate (50 ml). The combined organic layers were further washed withbrine (2×100 ml), dried (Na₂SO₄) and concentrated. The residue waspurified by flash chromatography on silica gel (heptane/ethyl acetate)to give 4-chloro-2′-ethoxy-6-methyl-[2,3′-bipyridin]-5-amine.

Preparation of7-chloro-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

A suspension of 4-chloro-2′-ethoxy-6-methyl-[2,3′-bipyridin]-5-amine(4.01 g, 12.2 mmol) and potassium acetate (2.98 g, 30.4 mmol) in toluene(84 ml) and acetic acid (28 ml) was stirred at ice bath temperature for5 minutes under an inert atmosphere. Isopentyl nitrite (2.71 g, 23.11mmol) was added dropwise for 5 minutes. After stirring at ice bathtemperature over 10 minutes a reflux condenser was inserted and themixture was heated to 35° C. for 2.5 hours. Most of the solvent wasremoved under vacuo. The obtained residue was suspended in ethyl acetate(350 ml) and washed with aqueous saturated NaHCO₃ (2×250 ml), brine (200ml), dried (Na₂SO₄) and concentrated. The residue was purified by flashchromatography on silica gel (heptane/ethyl acetate) to give7-chloro-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine.

Preparation of7-chloro-5-(2-ethoxypyridin-3-yl)-3-iodo-1H-pyrazolo[4,3-b]pyridine

A solution of7-chloro-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine (1.0 g,3.64 mmol) and N-iodo succinimide (1.11 g, 4.91 mmol) in DMF (50.0 ml)was stirred at room temperature for 15 minutes under an inert atmosphereafter which a reflux condenser was inserted and stirring continued at35° C. for 11 hours. The solution was diluted with ethyl acetate (350ml) and washed with aqueous 10% Na₂S₂O₃ (100 ml), aqueous % saturatedNaHCO₃ (2×150 ml) and brine (50 ml). The organic layer was dried(Na₂SO₄) and concentrated to deliver7-chloro-5-(2-ethoxypyridin-3-yl)-3-iodo-1H-pyrazolo[4,3-b]pyridinewhich was used without further purification.

Preparation of7-chloro-5-(2-ethoxypyridin-3-yl)-3-iodo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine

A solution of diisopropyl azodicarboxylate (1.59 g, 7.86 mmol) in THF(3.0 ml) was dropwise added to an ice cold solution of7-chloro-5-(2-ethoxypyridin-3-yl)-3-iodo-1H-pyrazolo[4,3-b]pyridine (1.0g, 2.25 mmol), isopropanol (0.60 ml, 7.86 mmol) and triphenylphosphine(2.06 g, 7.86 mmol) in THF (25 ml) under an inert atmosphere. Afterstirring at ice bath temperature for 0.5 hours, the solution was allowedto reach room temperature and stirring continued for 4.5 hours. Most ofthe solvent was removed under vacuo and the obtained residue wasdissolved in ethyl acetate (150 ml) and washed with aqueous saturatedNaHCO₃ (150 ml), brine (100 ml), dried (Na₂SO₄) and concentrated.Purification by flash chromatography on silica gel (elution gradientfrom heptane to ethyl acetate) delivered7-chloro-5-(2-ethoxypyridin-3-yl)-3-iodo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

Preparation of7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-vinyl-1H-pyrazolo[4,3-b]pyridine

N₂ was bubbled through a suspension of7-chloro-5-(2-ethoxypyridin-3-yl)-3-iodo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine(10 mg, 0.023 mmol), tributyl(vinyl)stannane (9.9 μl, 0.034 mmol),bis(triphenylphosphine) palladiuml(II) dichloride (4 mg, 5.7 μmol) in1,4-dioxane (0.30 ml) over 2 minutes. The mixture was stirred at 105° C.for 6.5 hours after which additional tributyl(vinyl)stannane (5.0 μl,0.017 mmol), bis(triphenylphosphine) palladiuml(II) dichloride (1.6 mg,2.3 μmol) and 1,4-dioxane (0.15 ml) were added. The mixture was degassedby bubbling N₂ over 2 minutes and reheated to 105° C. for 5 hours. Mostof the solvent was removed under vacuo. The obtained residue wasdissolved in ethyl acetate (20 ml), washed with brine (10 ml) and dried(Na₂SO₄). Concentration under vacuo delivered a residue which waspurified by flash chromatography on silica gel (elution gradient fromheptane to ethyl acetate) to deliver7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-vinyl-1H-pyrazolo[4,3-b]pyridine.

Preparation of1-(7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-3-yl)ethane-1,2-diol

A mixture of7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-vinyl-1H-pyrazolo[4,3-b]pyridine(10 mg, 0.03 mmol), osmium tetraoxide (as a 2.5 wt % in2-methyl-2-propanol) (37 μl, 2.9 μmol), N-methylmorpholine (as a 50%aqueous solution) (14 mg, 0.06 mmol) in THF (0.29 ml) and water (0.10ml) was stirred at room temperature for 24 hours. The reaction wasquenched at room temperature with aqueous 10% Na₂S₂O₃ (0.2 ml) and theresulting mixture was stirred for 5 minutes, diluted with brine (0.3 ml)and extracted with ethyl acetate (2×5 ml). The combined organic layerswere dried (Na₂SO₄) and concentrated to deliver crude1-(7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-3-yl)ethane-1,2-diolwhich was used without further purification.

Preparation of7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carbaldehyde

A mixture of1-(7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-3-yl)ethane-1,2-diol(9.0 mg, 0.024 mmol) and sodium periodate (7.7 mg, 0.04 mmol) in THF(0.25 ml) and water (55 μl) was stirred at room temperature for 40minutes after which sodium periodate (10.0 mg, 0.05 mmol) and 3 drops ofwater were added. After stirring for further 15 minutes, the resultingsuspension was diluted with ethyl acetate (5 ml) and stirred for 3minutes. The mixture was filtered through a short pad of Celite whichwas rinsed with ethyl acetate (2×5 ml). The combined filtrates werewashed with brine (5 ml), dried (Na₂SO₄) and concentrated to deliver7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carbaldehydewhich was used without further purification.

Preparation of(7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-3-yl)methanol

NaBH₄ (2.0 mg, 0.05 mmol) was added to an ice cold solution of7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carbaldehyde(4.0 mg, 0.01 mmol) in methanol (0.1 ml) under an inert atmosphere.After stirring for 5 minutes at ice bath temperature the resultingsolution was allowed to reach room temperature and stirring continuedfor 1 hour Recooled to ice bath temperature and quenched with a fewdrops of water. Most of the solvent was removed under vacuo. Theobtained residue was partitioned between ethyl acetate (15 ml) and brine(10 ml). The aqueous layer was back-extracted with ethyl acetate (5 ml).The combined organic layers were dried (Na₂SO₄) and concentrated. Theresidue was purified by flash chromatography on silica gel(heptane/ethyl acetate) to give(7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-3-yl)methanol.

Preparation of7-chloro-5-(2-ethoxypyridin-3-yl)-3-(fluoromethyl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine

Diethylaminosulfur trifluoride (5 μl, 0.04 mmol) was added to an icecold solution of(7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-3-yl)methanol(4.0 mg, 0.01 mmol) in CHCl₃ (0.2 ml). The reaction vial was capped andthe solution was stirred at 0° C. for 5 minutes after which the coolingbath was removed and stirring continued at room temperature for 12hours. The solution was diluted with ethyl acetate (25 ml) and washedwith aqueous saturated NaHCO₃ (2×15 ml), brine (10 ml), dried (Na₂SO₄)and concentrated. The residue was purified by flash chromatography onsilica gel (heptane/ethyl acetate) to give7-chloro-5-(2-ethoxypyridin-3-yl)-3-(fluoromethyl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

Preparation of7-chloro-3-(difluoromethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine

A solution of7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carbaldehyde(5.0 mg, 0.01 mmol) and diethylaminosulfur trifluoride (10 μl, 0.08mmol) in dichloromethane (0.15 ml) was stirred at room temperature for4.5 hours. under an inert atmosphere. The mixture was diluted with ethylacetate (20 ml) and washed with aqueous saturated NaHCO₃ (10 m) andbrine (10 ml). The organic layer was dried (Na₂SO₄) and concentrated.The residue was purified by flash chromatography on silica gel(heptane/ethyl acetate) to give7-chloro-3-(difluoromethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

Compounds of the Invention Example 1:5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

To a solution of5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine (100 mg,0.41 mmol) in NMP (2 mL) was added CsF (187 mg, 1.23 mmol, 45 μL) and(5-methyl-1,3,4-oxadiazol-2-yl)methanamine hydrochloride (74 mg, 0.49mmol). The mixture was stirred at 100° C. for 18 hours. Water (30 mL)was added and the mixture was extracted with ethyl acetate (30 mL×3).The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄ and concentrated. The crude mixture was purified by preparativeHPLC to give5-chloro-1-isopropyl-3-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(50 mg).

To a solution of5-chloro-1-isopropyl-3-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(50 mg, 70 μmol) and (2-ethoxypyridin-3-yl)boronic acid (21 mg, 0.13mmol) in dioxane (2 mL) and H₂O (0.7 mL) was added Cs₂CO₃ (57 mg, 175μmol) and Pd(1,1′-bis(diphenylphosphino)ferrocene)Cl₂ (10 mg, 14 μmol).The mixture was purged with nitrogen for 3 minutes then stirred at 100°C. for 30 minutes under microwave irradiation. Water (30 mL) was addedand the mixture was extracted with ethyl acetate (30 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by preparative TLC withdichloromethane:methanol=20:1 twice, and then the crude product wasfurther purified by preparative HPLC to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(6.1 mg).

¹H NMR (chloroform-d, 400 MHz) δ 8.28-8.26 (m, 1H), 8.19-8.18 (m, 1H),7.23 (s, 1H), 7.05-7.02 (m, 1H), 5.27 (brs, 1H), 4.96-4.90 (m, 1H), 4.71(d, J=1.2 Hz, 2H), 4.53-4.48 (m, 2H), 2.65 (s, 3H), 2.57 (s, 3H), 1.66(d, J=6.4 Hz, 6H), 1.43 (t, J=6.8 Hz, 3H). LC-MS (m/z) 408.2 (MH⁺);t_(R)=2.08 minutes (Method B).

The following examples were prepared in a similar manner

Example 2:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methylthiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (5-methylthiazol-2-yl)methanamine dihydrochloride and5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 500 MHz) δ 8.21-8.14 (m, 2H), 7.42 (d, J=1.4 Hz, 1H),7.21 (t, J=5.6 Hz, 1H), 7.11-7.05 (m, 2H), 5.23 (hept, J=6.4 Hz, 1H),4.75 (d, J=5.5 Hz, 2H), 4.31 (q, J=7.0 Hz, 2H), 2.48 (s, 3H), 2.35 (s,3H), 1.50 (d, J=6.4 Hz, 6H), 1.24 (t, J=7.1 Hz, 3H). LC-MS (m/z) 423(MH⁺); t_(R)=0.61 minutes (Method D).

Example 3:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methylisoxazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (5-methylisoxazol-3-yl)methanamine and5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 500 MHz) δ 8.28 (d, J=7.3 Hz, 1H), 8.29-8.17 (m,1H), 7.29 (s, 1H), 7.04 (m, 1H), 6.07 (s, 1H), 5.19 (brs, 1H), 4.90(hept, J=6.4 Hz, 1H), 4.59 (d, J=5.2 Hz, 2H), 4.50 (q, J=7.0 Hz, 2H),2.67 (s, 3H), 2.47 (s, 3H), 1.66 (d, J=6.1, 6H), 1.43 (q, J=7.1 Hz, 3H).LC-MS (m/z) 407.3 (MH⁺); t_(R)=0.54 minutes (Method E).

Example 4:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyloxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (2-methyloxazol-5-yl)methanamine and5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.21-8.15 (m, 2H), 7.14 (s, 1H), 7.09 (dd,J=7.3, 4.8 Hz, 1H), 6.90 (s, 1H), 6.82 (t, J=5.7 Hz, 1H), 5.16 (hept,J=6.4 Hz, 1H), 4.55 (d, J=5.5 Hz, 2H), 4.39 (q, J=7.0 Hz, 2H), 2.47 (s,3H), 2.37 (s, 3H), 1.45 (d, J=6.4 Hz, 6H), 1.26 (t, J=7.0 Hz, 3H). LC-MS(m/z) 407.1 (MH⁺); t_(R)=0.53 minutes (Method D).

Example 5:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyltriazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (2-methyl-2H-1,2,3-triazol-4-yl)methanamine and5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-de, 600 MHz) δ 8.21-8.15 (m, 2H), 7.64 (s, 1H), 7.10-7.08(m, 2H), 6.88 (t, J=5.6 Hz, 1H), 5.19 (hept, J=6.3 Hz, 1H), 4.59 (d,J=5.1 Hz, 2H), 4.34 (q, J=7.0 Hz, 2H), 4.11 (s, 3H), 2.48 (s, 3H), 1.48(d, J=5.7 Hz, 6H), 1.28-1.20 (t, J=7.0 Hz, 3H). LC-MS (m/z) 407.1 (MH⁺);t_(R)=0.55 minutes (Method D).

Example6:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methyltriazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-1,2,3-triazol-4-yl)methanamine and5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.21-8.14 (m, 2H), 7.90 (s, 1H), 7.13 (s,1H), 7.08 (dd, J=7.3, 4.9 Hz, 1H), 6.88 (t, J=5.7 Hz, 1H), 5.18 (hept,J=6.4 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 4.34 (q, J=7.0 Hz, 2H), 3.98 (s,3H), 2.47 (s, 3H), 1.47 (d, J=6.3 Hz, 6H), 1.25 (t, J=7.0 Hz, 3H). LC-MS(m/z) 407.3 (MH⁺); t_(R)=0.45 minutes (Method E).

Example 7:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1H-pyrazol-4-yl)methanamine hydrochloride and5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 600 MHz) δ 8.27 (dd, J=7.3, 2.0 Hz, 1H), 8.18 (dd,J=4.8, 1.9 Hz, 1H), 7.69 (s, 2H), 7.25 (s, 1H), 7.03 (dd, J=7.3, 4.9 Hz,1H), 4.76 (hept, J=6.4 Hz, 1H), 4.55 (brds, 1H), 4.46 (m, 4H), 2.63 (s,3H), 1.59 (d, J=6.5 Hz, 6H), 1.39 (t, J=7.0 Hz, 3H). LC-MS (m/z) 392.1(MH⁺); t_(R)=0.50 minutes (Method D).

Example 8:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (2-methyl-2H-tetrazol-5-yl)methanamine and5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27 (dd, J=7.2, 2.0 Hz, 1H), 8.18 (dd,J=5.2, 2.0 Hz, 1H), 7.26 (s, 1H), 7.04-7.01 (m, 1H), 5.33-5.31 (m, 1H),4.96-4.93 (m, 1H), 4.80 (d, J=5.2 Hz, 2H), 4.50 (q, J=6.8 Hz, 2H), 4.39(s, 3H), 2.65 (s, 3H), 1.67 (d, J=6.4 Hz, 6H), 1.44 (t, J=6.8 Hz, 3H).LC-MS (m/z) 408.1 (MH⁺); t_(R)=1.96 minutes (Method C).

Example 9:5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((1-methyl-H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-H-pyrazol-4-yl)methanamine and5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d6, 400 MHz): δ 8.18-8.16 (m, 2H), 7.60 (s, 1H), 7.41 (s,1H), 7.10-7.06 (m, 2H), 6.68-6.65 (m, 1H), 5.19-5.12 (m, 1H), 4.39-4.34(m, 4H), 3.77 (s, 3H), 2.46 (s, 3H), 1.15 (d, J=6.4 Hz, 6H), 1.25 (t,J=7.2 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺); t_(R)=2.50 minutes (Method B).

Example 10:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(3-methylisoxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (3-methylisoxazol-5-yl)methanamine and5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.28-8.26 (m, 1H), 8.15-8.18 (m, 1H),7.20 (s, 1H), 7.04-7.00 (m, 1H), 6.10 (s, 1H), 4.87 (brs, 2H), 4.66-4.65(m, 2H), 4.45 (q, J=7.2 Hz, 2H), 2.64 (s, 3H), 2.29 (s, 3H), 1.63 (d,J=6.8 Hz, 6H), 1.36 (t, J=7.2 Hz, 3H). LC-MS (m/z) 407.1 (MH⁺);t_(R)=2.05 minutes (Method C).

Example 11:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (2-methylthiazol-4-yl)methanamine and5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.26 (dd, JJJ=7.6, 2.0 Hz, 1H), 8.17(dd, J=4.8, 2.0 Hz, 1H), 7.18 (s, 1H), 7.05-7.01 (m, 2H), 5.40-5.27 (m,1H), 4.96-4.90 (m, 1H), 4.59 (d, J=5.2 Hz, 2H), 4.46 (q, J=7.2 Hz, 2H),2.75 (s, 3H), 2.65 (s, 3H), 1.65 (d, J=6.4 Hz, 6H), 1.38 (t, J=7.2 Hz,3H). LC-MS (m/z) 423 (MH⁺); t_(R)=1.90 minutes (Method A).

Example 12:1-cyclopropyl-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-H-pyrazol-4-yl)methanamine and5,7-dibromo-1-cyclopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26-8.23 (m, 1H), 8.19-8.17 (m, 1H),7.57 (s, 1H), 7.44 (s, 1H), 7.16 (s, 1H), 7.04-7.01 (m, 1H), 5.64 (brs,1H), 4.50-4.45 (m, 2H), 4.39 (d, J=4.4 Hz, 2H), 3.93 (s, 3H), 3.72-3.70(m, 1H), 2.61 (s, 3H), 1.46-1.38 (m, 5H), 1.16-1.11 (m, 2H). LC-MS (m/z)404.1 (MH⁺); t_(R)=1.88 minutes (Method C).

Example 13:5-(2-ethoxy-3-pyridyl)-N-[(1-methylpyrazol-4-yl)methyl]-1-propyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine dihydrochloride and5,7-dibromo-1-propyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.16-8.11 (m, 2H), 8.04 (s, 1H), 7.49(s, 1H), 7.37 (s, 1H), 7.17 (s, 1H), 6.97-6.94 (m, 1H), 4.42-4.32 (m,7H), 3.86 (s, 3H), 1.85 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H), 0.86(t, J=7.2 Hz, 3H). LC-MS (m/z) 392.2 (MH⁺); t_(R)=1.87 minutes (MethodC).

Example 14:5-(2-ethoxypyridin-3-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine and7-bromo-5-chloro-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Methanol-d₄, 600 MHz) δ 68.18-8.14 (m, 2H), 7.95 (dd, J=7.3, 2.0Hz, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.08-7.04 (m, 2H), 6.24-6.17 (m,1H), 5.24-5.18 (m, 2H), 5.15-5.08 (m, 2H), 4.45 (s, 2H), 4.38 (q, J=7.0Hz, 2H), 3.85 (s, 3H), 1.26 (t, J=7.0 Hz, 3H). LC-MS (m/z) 406.2 (MH⁺);t_(R)=0.41 minutes (Method D).

Example 15:5-(2-ethoxypyridin-3-yl)-1-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(racemic)

Prepared from 1-(1-methyl-H-pyrazol-4-yl)ethan-1-amine and7-bromo-5-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 500 MHz) δ 8.24-8.17 (m, 2H), 8.09 (s, 1H), 7.54(s, 1H), 7.39 (s, 1H), 7.17 (s, 1H), 7.03 (dd, J=7.3, 5.1 Hz, 1H), 4.84(m, 1H), 4.73 (d, J=5.9 Hz, 1H), 4.54-4.37 (m, 2H), 4.35 (s, 3H), 3.91(s, 3H), 1.72 (d, J=7.0 Hz 3H), 1.36 (t, J=6.5 Hz, 3H). LC-MS (m/z)378.2 (MH⁺); t_(R)=0.44 minutes (Method D).

Example 16:5-(2-ethoxypyridin-3-yl)-1-methyl-N-((1-methyl-H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine and5,7-dibromo-1-methyl-H-pyrazolo[4,3-b]pyridine

¹H NMR (Methanol-d₄, 400 MHz) δ 8.15-8.14 (m, 1H), 7.93-7.92 (m, 2H),7.60 (s, 1H), 7.50 (s, 1H), 7.038 (dd, J=4.8 Hz, J=6.8 Hz, 1H), 6.94 (s,1H), 4.46 (s, 2H), 4.40-4.34 (m, 6H), 3.83 (s, 3H), 1.25 (t, J=6.8 Hz,3H). LC-MS (m/z) 364.1 (MH⁺); t_(R)=1.71 minutes (Method C).

Example 17:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methylimidazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-H-imidazol-2-yl)methanamine and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.19 (dd, J=4.9, 2.0 Hz, 1H), 8.09-8.12 (m,2H), 7.35 (s, 1H), 7.13-7.05 (m, 2H), 6.83-6.76 (m, 2H), 5.25 (hept,J=6.5 Hz, 1H), 4.56 (d, J=4.9 Hz, 2H), 4.42 (q, J=7.0 Hz, 2H), 3.71 (s,3H), 1.51 (d, J=6.4 Hz, 6H), 1.38 (t, J=7.0 Hz, 3H). LC-MS (m/z) 392.1(MH⁺); t_(R)=0.35 minutes (Method D).

Example 18:5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1-methyl-H-pyrazol-5-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-H-pyrazol-5-yl)methanamine dihydrochloride and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.20-8.12 (m, 3H), 7.33 (d, J=1.8 Hz, 1H),7.14 (s, 1H), 7.08 (dd, J=7.4, 4.8 Hz, 1H), 6.89 (t, J=5.4 Hz, 1H), 6.19(d, J=1.8 Hz, 1H), 5.29 (hept, J=6.5 Hz, 1H), 4.59 (d, J=5.3 Hz, 2H),4.36 (q, J=7.0 Hz, 2H), 3.88 (s, 3H), 1.50 (d, J=6.3 Hz, 6H), 1.24 (t,J=7.0 Hz, 3H). LC-MS (m/z) 392.1 (MH⁺); t_(R)=0.49 minutes (Method D).

Example 19:5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1-methyl-H-pyrazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-H-pyrazol-3-yl)methanamine and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.19-8.13 (m, 2H), 8.09 (s, 1H), 7.59 (d,J=2.2 Hz, 1H), 7.14 (s, 1H), 7.07 (dd, J=7.4, 4.8 Hz, 1H), 6.85 (t,J=5.7 Hz, 1H), 6.17 (d, J=2.1 Hz, 1H), 5.27 (hept, J=6.4 Hz, 1H), 4.46(d, J=5.6 Hz, 2H), 4.36 (q, J=7.0 Hz, 2H), 3.78 (s, 3H), 1.50 (d, J=6.3Hz, 6H), 1.29 (t, J=7.0 Hz, 3H). LC-MS (m/z) 392.1 (MH⁺); t_(R)=0.54minutes (Method D).

Example20:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(thiazol-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared from thiazol-2-ylmethanamine hydrochloride and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine

¹H NMR (DMSO-d₆, 600 MHz). δ 8.18-8.13 (m, 3H), 7.78 (d, J=3.3 Hz, 1H),7.62 (d, J=3.3 Hz, 1H), 7.32 (t, J=5.7 Hz, 1H), 7.12 (s, 1H), 7.06 (dd,J=6.9, 5.4 Hz, 1H), 5.32 (hept, J=6.5 Hz, 1H), 4.86 (d, J=5.6 Hz, 2H),4.29 (q, J=7.0 Hz, 2H), 1.54 (d, J=6.4 Hz, 6H), 1.21 (t, J=7.0 Hz, 3H).LC-MS (m/z) 395 (MH⁺); t_(R)=0.54 minutes (Method D).

Example 21:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methylimidazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-imidazol-4-yl)methanamine and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.19-8.13 (m, 2H), 8.09 (s, 1H), 7.52 (s,1H), 7.15 (s, 1H), 7.07 (dd, J=7.3, 4.9 Hz, 1H), 6.96 (s, 1H), 6.76 (t,J=5.5 Hz, 1H), 5.25 (hept, J=6.5 Hz, 1H), 4.40 (d, J=5.4 Hz, 2H), 4.35(q, J=7.0 Hz, 2H), 3.57 (s, 3H), 1.50 (d, J=6.3 Hz, 6H), 1.27 (t, J=7.0Hz, 3H). LC-MS (m/z) 392.1 (MH⁺); t_(R)=0.39 minutes (Method D).

Example22:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(4-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared from pyridin-4-ylmethanamine and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Methanol-d₄, 600 MHz) δ 8.52-8.48 (m, 2H), 8.11 (dd, J=5.0, 1.9Hz, 1H), 8.06 (s, 1H), 7.90 (dd, J=7.4, 2.0 Hz, 1H), 7.51-7.47 (m 2H),7.01 (dd, J=7.4, 4.9 Hz, 1H), 6.74 (s, 1H), 5.28 (hept, J=6.5 Hz, 1H),4.72 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 1.64 (d, J=6.4 Hz, 6H), 1.07 (t,J=7.0 Hz, 3H). LC-MS (m/z) 389.1 (MH⁺); t_(R)=0.38 minutes (Method D).

Example 23:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(m-tolylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared from m-tolylmethanamine hydrochloride and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.22-8.17 (m, 3H), 7.33-7.19 (m, 5H),7.03-7.00 (m, 1H), 4.89-4.86 (m, 2H), 4.53 (d, J=5.2 Hz, 2H), 4.42 (q,J=7.2 Hz, 2H), 2.39 (s, 3H), 1.65 (d, J=6.4 Hz, 6H), 1.33 (t, J=7.2 Hz,3H). LC-MS (m/z) 402.1 (MH⁺); t_(R)=2.57 minutes (Method F).

Example 24:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(p-tolylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared from p-tolylmethanamine and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.23-8.17 (m, 3H), 7.34-7.32 (m, 2H),7.24-7.22 (m, 3H), 7.03-7.00 (m, 1H), 4.89-4.74 (m, 2H), 4.52 (d, J=4.8Hz, 2H), 4.42 (q, J=6.8 Hz, 2H), 2.39 (s, 3H), 1.65 (d, J=6.8 Hz, 6H),1.35 (t, J=6.8 Hz, 3H). LC-MS (m/z) 402.1 (MH⁺); t_(R)=2.17 minutes(Method A).

Example 25:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine dihydrochloride and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.22-8.16 (m, 3H), 7.57 (s, 1H), 7.44(s, 1H), 7.24 (s, 1H), 7.03-7.00 (m, 1H), 4.82-4.77 (m, 1H), 4.60 (brs,1H), 4.46 (q, J=7.2 Hz, 2H), 4.39 (d, J=4.8 Hz, 2H), 3.93 (s, 3H), 1.62(d, J=6.4 Hz, 6H), 1.39 (t, J=7.2 Hz, 3H). LC-MS (m/z) 392.2 (MH⁺);t_(R)=1.86 minutes (Method C).

Example26:5-(2-ethoxy-3-pyridyl)-1-ethyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine and5,7-dibromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.22-8.11 (m, 3H), 7.56 (s, 1H), 7.43(s, 1H), 7.23 (s, 1H), 7.03-7.00 (m, 1H), 4.56-4.39 (m, 7H), 3.92 (s,3H), 1.51 (t, J=7.2 Hz, 3H), 1.38 (t, J=7.2 Hz, 3H). LC-MS (m/z) 378.2(MH⁺); t_(R)=1.79 minutes (Method G).

Example 27:5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine and5,7-dibromo-3-methyl-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.30-8.28 (m, 1H), 8.20-8.18 (m, 1H),7.54 (s, 1H), 7.43 (s, 1H), 7.32 (s, 1H), 7.05-7.02 (m, 1H), 5.85-5.75(m, 1H), 5.55 (brs, 1H), 5.18-5.11 (m, 4H), 4.51-4.45 (m, 2H), 4.41 (d,J=4.8 Hz, 2H), 3.92 (s, 3H), 2.64 (s, 3H), 1.40 (t, J=7.2 Hz, 3H). LC-MS(m/z) 420.1 (MH⁺); t_(R)=1.99 minutes (Method B).

Example28:5-(2-ethoxy-3-pyridyl)-1,3-dimethyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine and5,7-dichloro-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.28-8.26 (m, 1H), 8.19-8.18 (m, 1H),7.56 (s, 1H), 7.44 (s, 1H), 7.21 (s, 1H), 7.04-7.01 (m, 1H), 4.63 (brs,1H), 4.47 (q, J=6.8 Hz, 2H), 4.38 (d, J=4.8 Hz, 2H), 4.23 (s, 3H), 3.92(s, 3H), 2.62 (s, 3H), 1.39 (t, J=7.2 Hz, 3H). LC-MS (m/z) 378.2 (MH⁺);t_(R)=1.93 minutes (Method B).

Example 29:5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((4-methylthiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

To a solution of5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(50 mg, 0.16 mmol) in THF (3 mL) was added Ti(i-PrO)₄ (91 mg, 0.32 mmol,95 μL) and 4-methylthiazole-2-carbaldehyde (41 mg, 0.32 mmol, 35 μL).The mixture was stirred at 50° C. for 18 hours. The reaction mixture wascooled to 0° C., then NaBH₄ (30 mg, 0.80 mmol) was added into themixture slowly and the reaction was stirred at 0° C. for 10 min. Water(2 mL) was added to quench the reaction, the resulting mixture wasfiltered and the residue was washed with ethyl acetate (20 mL×2). Thecombined filtrates were washed with brine (10 mL), dried over Na₂SO₄,and concentrated. The residue was purified by column chromatography(SiO₂, petroleum ether:ethyl acetate=2:1 to 1:1) followed bypurification by preparative HPLC to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((4-methylthiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(14 mg).

¹H NMR (Chloroform-d, 400 MHz) δ 8.26-8.24 (m, 1H), 8.18-8.17 (m, 1H),7.19 (s, 1H), 7.03-7.00 (m, 1H), 6.87 (s, 1H), 5.01-4.95 (m, 1H), 4.82(d, J=4.8 Hz, 2H), 4.47-4.42 (q, J=7.2 Hz, 2H), 2.66 (s, 3H), 2.48 (s,3H), 1.68 (d, J=6.4 Hz, 6H), 1.37 (t, J=7.2 Hz, 3H). LC-MS (m/z) 423.0(MH⁺); t_(R)=1.92 minutes (Method C).

The following examples were prepared in a similar manner

Example 30:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 3-methyl-1,2,4-oxadiazole-5-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27 (dd, J=7.2, 2.0 Hz, 1H), 8.19-8.18(m, 1H), 7.17 (s, 1H), 7.05-7.02 (m, 1H), 4.95 (brs, 1H), 4.76 (d, J=4.8Hz, 2H), 4.49 (q, J=6.8 Hz, 2H), 2.65 (s, 3H), 2.44 (s, 3H), 1.67 (d,J=6.4 Hz, 6H), 1.42 (t, J=6.8 Hz, 3H). LC-MS (m/z) 408.2 (MH⁺);t_(R)=2.31 minutes (Method B).

Example 31:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 1-methyl-1H-1,2,4-triazole-3-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27 (dd, J=1.6, 7.2 Hz, 1H), 8.18 (dd,J=1.6, 4.8 Hz, 1H), 8.05 (s, 1H), 7.22 (s, 1H), 7.04-7.01 (m, 1H), 5.50(brs, 1H), 5.01-4.96 (m, 1H), 4.58 (d, J=4.8 Hz, 2H), 4.50 (q, J=7.2 Hz,2H), 3.95 (s, 3H), 2.66 (s, 3H), 1.66 (d, J=6.0 Hz, 6H), 1.45 (t, J=7.2Hz, 3H). LC-MS (m/z) 407.1 (MH⁺); t_(R)=1.87 minutes (Method C).

Example32:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 2-methylthiazole-5-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.17-8.25 (m, 1H), 8.19-8.18 (m, 1H),7.62 (s, 1H), 7.26 (s, 1H), 7.05-7.02 (m, 1H), 4.83-4.80 (m, 1H), 4.70(s, 2H), 4.48 (q, J=7.2 Hz, 2H), 2.71 (s, 3H), 2.65 (s, 3H), 1.62 (d,J=6.4 Hz, 6H), 1.40 (t, J=7.2 Hz, 3H). LC-MS (m/z) 423 (MH⁺); t_(R)=1.80minutes (Method A).

Example33:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 5-methyl-1,3,4-thiadiazole-2-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.32-8.29 (m, 1H), 8.22-8.20 (m, 1H),7.30 (s, 1H), 7.07-7.04 (m, 1H), 5.51 (brs, 1H), 4.97 (d, J=5.2 Hz, 2H),4.57-4.48 (m, 2H), 2.82 (s, 3H), 2.69 (s, 3H), 1.69 (d, J=6.4 Hz, 6H),1.42 (t, J=7.2 Hz, 3H). LC-MS (m/z) 424 (MH⁺); t_(R)=2.14 minutes(Method B).

Example 34:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-3-thienyl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 5-methylthiophene-3-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.28-8.26 (m, 1H), 8.18-8.17 (m, 1H),7.22 (s, 1H), 7.04-7.01 (m, 2H), 6.80 (s, 1H), 4.84-4.77 (m, 1H), 4.66(brs, 1H), 4.48-4.43 (m, 4H), 2.65 (s, 3H), 2.51 (s, 3H), 1.62 (d, J=6.8Hz, 6H), 1.38 (t, J=7.2 Hz, 3H). LC-MS (m/z) 422 (MH⁺); t=2.21 minutes(Method H).

Example 35:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methyl-2-thienyl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 4-methylthiophene-2-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27 (dd, J=7.6, 1.6 Hz, 1H), 8.18 (dd,J=4.8, 2.0 Hz, 1H), 7.26 (s, 1H), 7.04-7.01 (m, 1H), 6.92 (s, 1H), 6.87(s, 1H), 4.86-4.81 (m, 1H), 4.72 (brs, 1H), 4.66-4.65 (m, 2H), 4.47 (q,J=7.2 Hz, 2H), 2.65 (s, 3H), 2.27 (s, 3H), 1.62 (d, J=6.4 Hz, 6H), 1.39(t, J=7.2 Hz, 3H). LC-MS (m/z) 422.1 (MH⁺); t=1.78 minutes (Method 1).

Example 36:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-2-thienyl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 5-methylthiophene-2-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.28-8.25 (m, 1H), 8.18-8.17 (m, 1H),7.25 (s, 1H), 7.04-7.01 (m, 1H), 6.90-6.89 (m, 1H), 6.67-6.66 (s, 1H),4.86-4.81 (m, 1H), 4.72 (brs, 1H), 4.63-4.62 (m, 2H), 4.48 (q, J=6.8 Hz,2H), 2.65 (s, 3H), 2.49 (s, 3H), 1.62 (d, J=6.4 Hz, 6H), 1.39 (t, J=7.2Hz, 3H). LC-MS (m/z) 422 (MH⁺); t_(R)=1.78 minutes (Method 1).

Example 37:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyloxazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 2-methyloxazole-4-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.26-8.24 (m, 1H), 8.17-8.16 (m, 1H),7.53 (s, 1H), 7.17 (s, 1H), 7.03-7.00 (m, 1H), 5.01 (brs, 1H), 4.88-4.83(m, 1H), 4.49-4.44 (m, 2H), 4.39 (d, J=5.2 Hz, 2H), 2.64 (s, 3H), 2.48(s, 3H), 1.62 (d, J=6.8 Hz, 6H), 1.38 (t, J=7.2 Hz, 3H). LC-MS (m/z)407.1 (MH⁺); t_(R)=2.03 minutes (Method C).

Example 38:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyloxazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 5-methyloxazole-2-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27-8.25 (m, 1H), 8.19-8.17 (m, 1H),7.17 (s, 1H), 7.04-7.01 (m, 1H), 6.75 (s, 1H), 5.41 (brs, 1H), 4.99-4.95(m, 1H), 4.55 (d, J=4.8 Hz, 2H), 4.49 (q, J=7.2 Hz, 2H), 2.65 (s, 3H),2.35 (s, 3H), 1.67 (d, J=6.4 Hz, 6H), 1.44 (t, J=7.2 Hz, 3H). LC-MS(m/z) 407.1 (MH⁺); t_(R)=2.06 minutes (Method C).

Example 39:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared from 1H-pyrazole-3-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.25-8.23 (m, 1H), 8.18-8.16 (m, 1H),7.58 (d, J=2.4 Hz, 1H), 7.19 (s, 1H), 7.03-7.00 (m, 1H), 6.35 (d, J=2.4Hz, 1H), 5.31 (brs, 1H), 4.93-4.87 (m, 1H), 4.57 (d, J=4.8 Hz, 2H),4.50-4.45 (m, 2H), 2.65 (s, 3H), 1.63 (d, J=6.4 Hz, 6H), 1.41 (t, J=7.2Hz, 3H). LC-MS (m/z) 392.1 (MH⁺); t_(R)=1.92 minutes (Method C).

Example40:5-(2-ethoxy-3-pyridyl)-N-(1H-imidazol-4-ylmethyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared from 1H-imidazole-4-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.24-8.22 (m, 1H), 8.17-8.15 (m, 1H),7.65 (m, 1H), 7.19 (m, 1H), 7.03-7.00 (m, 2H), 5.27 (brs, 1H), 4.92-4.86(m, 1H), 4.49-4.44 (m, 4H), 2.64 (s, 3H), 1.61 (d, J=6.4 Hz, 6H), 1.40(t, J=7.2 Hz, 3H). LC-MS (m/z) 392.1 (MH⁺); t_(R)=1.52 minutes (MethodC).

Example 41:N-benzyl-5-(2-ethoxy-3-pyridyl)-1-isopropyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared from benzaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (DMSO-d, 600 MHz) δ 8.16-8.07 (m, 3H), 7.43-7.38 (m, 2H), 7.35(dd, J=8.4, 7.0 Hz, 2H), 7.27-7.21 (m, 1H), 7.04 (dd, J=7.4, 4.9 Hz,2H), 6.96 (s, 1H), 5.34 (hept, J=6.4 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H),4.23 (q, J=7.0 Hz, 2H), 1.56-1.45 (d, J=6.4 Hz, 6H), 1.13 (t, J=7.0 Hz,3H). LC-MS (m/z) 388 (MH⁺); t_(R)=0.66 minutes (Method D).

Example 42:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methylisoxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 3-methylisoxazole-5-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (DMSO-d, 600 MHz) δ 8.25-8.17 (m, 3H), 7.16-7.11 (m, 2H), 7.08(t, J=5.8 Hz, 1H), 6.31 (s, 1H), 5.31 (hept, J=6.5 Hz, 1H), 4.71 (d,J=5.7 Hz, 2H), 4.40 (q, J=7.0 Hz, 2H), 2.23 (s, 3H), 1.56 (d, J=6.5 Hz,6H), 1.29 (t, J=7.0 Hz, 3H). LC-MS (m/z) 393.1 (MH⁺); t_(R)=0.55 minutes(Method D).

Example 43:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 5-methyl-1,2,4-oxadiazole-3-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (DMSO-d, 600 MHz) δ 8.20-8.10 (m, 3H), 7.13 (s, 1H), 7.08 (dd,J=7.4, 4.9 Hz, 1H), 7.00 (t, J=5.9 Hz, 1H), 5.26 (hept, J=6.4 Hz, 1H),4.66 (d, J=5.8 Hz, 2H), 4.36 (q, J=7.0 Hz, 2H), 2.56 (s, 3H), 1.50 (d,J=6.4 Hz, 6H), 1.28 (t, J=7.0 Hz, 3H). LC-MS (m/z) 394 (MH⁺); t=0.54minutes (Method D).

Example 44:N-[(1,5-dimethylpyrazol-3-yl)methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared from 1,5-dimethyl-1H-pyrazole-3-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Methanol-d₄, 600 MHz) δ 8.17 (dd, J=5.0, 2.0 Hz, 1H), 8.04 (s,1H), 7.94 (dd, J=7.3, 1.9 Hz, 1H), 7.07 (dd, J=7.3, 4.9 Hz, 1H), 6.98(s, 1H), 6.07 (s, 1H), 5.22 (hept, J=6.4 Hz, 1H), 4.53 (d, J=1.5 Hz,2H), 4.39 (q, J=7.0 Hz, 2H), 3.75 (s, 3H), 2.26 (s, 3H), 1.63 (d, J=6.5Hz, 6H), 1.30 (t, J=7.1 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺); t_(R)=0.60minutes (Method D).

Example 45:3-(1-isopropyl-3-methyl-7-(((1-methyl-H-pyrazol-4-yl)methyl)amino)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpyridin-2(1H)-one

Prepared from 1-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.28-8.26 (m, 1H), 8.19-8.18 (m, 1H),7.44-7.42 (m, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.19 (s, 1H), 7.05-7.02 (m,1H), 6.66 (d, J=9.6 Hz, 1H), 4.82-4.76 (m, 1H), 4.56 (brs, 1H),4.47-4.42 (m, 2H), 4.29 (d, J=5.2 Hz, 2H), 3.56 (s, 3H), 2.65 (s, 3H),1.62 (d, J=6.4 Hz, 6H), 1.35 (t, J=7.2 Hz, 3H). LC-MS (m/z) 433.1 (MH⁺);t_(R)=1.86 min (Method C).

Example 46:5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((2-methyl-1H-imidazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from 2-methyl-1H-imidazole-4-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) 8.25-8.23 (m, 1H), 8.17-8.15 (m, 1H),7.19 (s, 1H), 7.02-6.99 (m, 1H), 6.89 (s, 1H), 5.19 (brs, 1H), 4.90-4.85(m, 1H), 4.49-4.41 (m, 4H), 2.63 (s, 3H), 2.43 (s, 3H), 1.61 (d, J=6.8Hz, 6H), 1.40 (t, J=7.2 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺); t_(R)=1.60 min(Method C).

Example 47:5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((5-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from 5-methyl-1H-pyrazole-3-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27-8.25 (m, 1H), 8.19-8.17 (m, 1H),7.20 (s, 1H), 7.04-7.01 (m, 1H), 6.08 (s, 1H), 5.29 (brs, 1H), 4.94-4.87(m, 1H), 4.51-4.46 (m, 4H), 2.65 (s, 3H), 2.35 (s, 3H), 1.63 (d, J=6.8Hz, 6H), 1.42 (t, J=7.2 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺); t_(R)=1.90 min(Method B).

Example48:5-(2-ethoxypyridin-3-yl)-1-ethyl-3-methyl-N-((1-methyl-H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from(1-methyl-1H-pyrazol-4-yl)methanamine and5,7-dibromo-1-ethyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.28-8.26 (m, 1H), 8.19-8.17 (m, 1H),7.56 (s, 1H), 7.43 (s, 1H), 7.23 (s, 1H), 7.04-7.01 (m, 1H), 4.53 (brs,1H), 4.50-4.45 (m, 4H), 4.40 (d, J=4.8 Hz, 2H), 3.92 (s, 3H), 2.63 (s,3H), 1.47 (t, J=7.2 Hz, 3H), 1.39 (t, J=7.2 Hz, 3H). LC-MS: LC-MS (m/z)392.1 (MH⁺); to =1.72 min (Method F).

Example49:3-(1-isopropyl-3-methyl-7-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpyridin-2(1H)-one

A mixture of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(60 mg, 0.17 mmol), 3-bromo-1-methylpyridin-2(1H)-one (62 mg, 0.33mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride(24 mg, 33 mmol), Cs₂CO₃ (108 mg, 0.33 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (84 mg, 0.33mmol) in dioxane (3 mL) was degassed and purged with N₂ 3 times, andthen the mixture was stirred at 100° C. for 1 hour under microwaveirradiation. Then water (30 mL) was added and the mixture was extractedwith ethyl acetate (30 mL×3). The combined organic layers were washedwith brine (20 mL), dried over Na₂SO₄ and concentrated. The crudeproduct was purified by preparative HPLC to give3-(1-isopropyl-3-methyl-7-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpyridin-2(1H)-one.

¹H NMR (Chloroform-d, 400 MHz) δ 8.45-8.42 (m, 1H), 7.82-7.80 (m, 1H),7.56-7.54 (m, 2H), 7.44-7.43 (m, 1H), 6.43-6.41 (m, 1H), 4.84-4.82 (m,1H), 4.48 (s, 2H), 3.92 (s, 3H), 3.68 (s, 3H), 2.63 (s, 3H) 1.57 (d,J=6.8 Hz, 6H). LC-MS (m/z) 392.1 (MH⁺); t_(R)=1.76 min (Method B).

Example 50:5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((4-methyloxazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine2,2,2-trifluoroacetate

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 4-methyloxazole-2-carbaldehyde.

¹H NMR (DMSO-de, 600 MHz) δ 8.37 (dd, J=4.9, 1.9 Hz, 1H), 8.03 (dd,J=7.5, 1.9 Hz, 1H), 7.81 (s, 1H), 7.22 (dd, J=7.5, 4.9 Hz, 1H), 7.11 (s,1H), 6.64 (bds, 1H), 5.29 (p, J=6.3 Hz, 1H), 4.91 (d, J=5.6 Hz, 2H),4.37 (q, J=7.0 Hz, 2H), 2.54 (s, 3H), 2.03 (s, 3H), 1.50 (d, J=6.3 Hz,6H), 1.26 (t, J=7.0 Hz, 3H). LC-MS (m/z) 407.4 (MH⁺); t_(R)=0.52 minutes(Method E).

Example 51:N-((1,2-dimethyl-1H-imidazol-4-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine2,2,2-trifluoroacetate

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1,2-dimethylimidazole-4-carbaldehyde.

¹H NMR (DMSO-de, 600 MHz) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.61 (s, 1H),7.23-7.17 (m, 1H), 7.09 (s, 1H), 6.66 (bds, 1H), 5.30 (m, 1H), 4.85 (m,2H), 4.36 (q, J=7.0 Hz, 2H), 3.77 (s, 3H), 2.58 (s, 3H), 2.53 (s, 3H),1.50 (d, J=6.3 Hz, 6H), 1.19 (t, J=7.0 Hz, 3H). LC-MS (m/z) 420.4 (MH⁺);t_(R)=0.33 minutes (Method E).

Example 52:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-methyl-1,2,4-oxadiazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27-8.25 (m, 1H), 8.19-8.18 (m, 1H),7.23 (s, 1H), 7.04-7.01 (m, 1H), 5.23 (brs, 1H), 4.94-4.91 (m, 1H), 4.63(d, J=5.2 Hz, 2H), 4.52-4.47 (m, 2H), 2.65 (s, 3H), 2.64 (s, 3H), 1.66(d, J=6.4 Hz, 6H), 1.44 (t, J=6.8 Hz, 3H). LC-MS (m/z) 408.4 (MH⁺);t_(R)=0.49 minutes (Method E).

Example 53:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1,2,4-oxadiazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1,2,4-oxadiazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz) δ 8.78 (s, 1H), 8.27-8.25 (m, 1H),8.19-8.17 (m, 1H), 7.25 (s, 1H), 7.04-7.01 (m, 1H), 5.25 (brs, 1H),4.96-4.90 (m, 1H), 4.74 (d, J=4.4 Hz, 2H), 4.52-4.47 (m, 2H), 2.65 (s,3H), 1.66 (d, J=6.4 Hz, 6H), 1.43 (t, J=7.2 Hz, 3H). LC-MS (m/z) 394.4(MH⁺); t_(R)=0.47 minutes (Method E).

Example 54:IV-[(1,5-dimethylpyrazol-3-yl)methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1,5-dimethylpyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d 400 MHz) δ 8.26 (dd, J=2.0, 7.6 Hz, 1H), 8.18 (dd,J=2.0, 8.4 Hz, 1H), 7.18 (s, 1H), 7.03 (dd, J=5.2, 7.6 Hz, 1H), 6.03 (s,1H), 5.29 (brs, 1H), 4.95-4.88 (m, 1H), 4.51-4.44 (m, 4H), 3.79 (s, 3H),2.65 (s, 3H), 2.29 (s, 3H), 1.64 (d, J=6.8 Hz, 6H), 1.42 (t, J=7.6 Hz,3H). LC-MS (m/z) 420.4 (MH⁺); t_(R)=0.53 minutes (Method E).

Example55:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1H-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-methyl-1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz) δ 8.23 (dd, J=2.0, 7.6 Hz, 1H), 8.17 (dd,J=2.0, 5.2 Hz, 1H), 7.19 (s, 1H), 7.01 (dd, J=5.2, 7.6 Hz, 1H), 5.70(brs, 1H), 5.00 (brs, 1H), 4.61 (br s, 2H), 4.48 (q, J=7.2 Hz, 2H), 2.64(s, 3H), 2.48 (s, 3H), 1.65 (d, J=6.4 Hz, 6H), 1.43 (t, J=7.2 Hz, 3H).LC-MS (m/z) 407.1 (MH⁺); t_(R)=1.86 minutes (Method C).

Example56:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-methyl-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz) δ 8.24-8.17 (m, 3H), 8.06 (s, 1H), 7.23(s, 1H), 7.04-7.01 (m, 1H), 5.61 (brs, 1H), 5.08-5.01 (m, 1H), 4.60 (d,J=4.4 Hz, 2H), 4.50 (q, J=7.2 Hz, 2H), 3.95 (s, 3H), 1.70 (d, J=6.4 Hz,6H), 1.46 (t, J=7.2 Hz, 3H). LC-MS (m/z) 393.4 (MH⁺); t=0.41 minutes(Method E).

Example 57:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz) δ 8.23-8.17 (m, 3H), 7.61 (d, J=2.4 Hz,1H), 7.22 (s, 1H), 7.04-7.01 (m, 1H), 6.38 (d, J=2.4 Hz, 1H), 5.46 (brs,1H), 5.02-4.95 (m, 1H), 4.59 (d, J=4.4 Hz, 2H), 4.49 (q, J=7.2 Hz, 2H),1.67 (d, J=6.8 Hz, 6H), 1.43 (t, J=7.2 Hz, 3H). LC-MS (m/z) 378.3 (MH⁺);t_(R)=0.43 minutes (Method E).

Example 58:5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((1-methyl-H-imidazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine2,2,2-trifluoroacetate

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine and(1-methyl-1H-imidazol-4-yl)methanamine.

¹H NMR (DMSO-d, 600 MHz) δ 8.99 (s, 1H), 8.55 (bds, 1H), 8.39 (dd,J=5.0, 1.9 Hz, 1H), 8.02 (dd, J=7.4, 1.9 Hz, 1H), 7.67 (s, 1H), 7.23(dd, J=7.4, 5.0 Hz, 1H), 7.04 (s, 1H), 5.29 (p, J=6.4 Hz, 1H), 4.91 (d,J=5.8 Hz, 2H), 4.36 (t, J=7.0 Hz, 2H), 3.82 (s, 3H), 2.55 (s, 3H), 1.51(d, J=6.4 Hz, 6H), 1.21 (t, J=7.0 Hz, 3H). LC-MS (m/z) 406.4 (MH⁺);t_(R)=0.34 minutes (Method E).

Example 59:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1,3,4-oxadiazol-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine and(1,3,4-oxadiazol-2-yl)methanamine hydrobromide.

¹H NMR (Chloroform-d, 400 MHz) δ 8.42-8.37 (m, 2H), 8.24-8.22 (m, 1H),7.88 (s, 1H), 7.10-7.08 (m, 2H), 4.86-4.79 (m, 1H), 4.52 (d, J=7.2 Hz,2H), 4.33 (s, 2H), 2.71 (s, 3H), 1.55 (d, J=6.8 Hz, 6H), 1.45 (t, J=7.2Hz, 3H). LC-MS (m/z) 394.3 (MH⁺); t_(R)=0.61 minutes (Method E).

Example 60:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine and(1-methyl-1H-pyrazol-3-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27-8.25 (m, 1H), 8.18-8.17 (m, 1H),7.37 (d, J=2.0 Hz, 1H), 7.20 (s, 1H), 7.04-7.01 (m, 1H), 6.26 (d, J=2.0Hz, 1H), 5.25 (brs, 1H), 4.95-4.88 (m, 1H), 4.51-4.46 (m, 4H), 3.93 (s,3H), 2.65 (s, 3H), 1.64 (d, J=6.4 Hz, 6H), 1.42 (t, J=6.8 Hz, 3H). LC-MS(m/z) 406.4 (MH⁺); t_(R)=0.50 minutes (Method E).

Example 61:5-(1,3-dimethylpyrazol-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5-chloro-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amineand1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole.

¹H NMR (Chloroform-d, 400 MHz): δ 7.75 (s, 1H), 7.55 (s, 1H), 7.40 (s,1H), 6.56 (s, 1H), 4.74-4.67 (m, 1H), 4.54 (brs, 1H), 4.37 (d, J=4.8 Hz,2H), 3.92 (s, 3H), 3.87 (s, 3H), 2.60 (s, 3H), 2.50 (s, 3H), 1.56 (d,J=6.4 Hz, 6H). LC-MS (m/z) 379.4 (MH⁺); t_(R)=0.38 minutes (Method E).

Example 62:1-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5-chloro-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amineand (2-methoxy-3-pyridyl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz) δ 8.21-8.17 (m, 2H), 7.57 (s, 1H), 7.45(s, 1H), 7.08-7.04 (m 2H), 4.79-4.73 (m, 1H), 4.57 (brs, 1H), 4.39 (d,J=4.8 Hz, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 2.64 (s, 3H), 1.59 (d, J=6.4Hz, 6H). LC-MS (m/z) 392.4 (MH⁺); t_(R)=0.43 minutes (Method E).

Example 63:1-isopropyl-5-(2-methoxyphenyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5-chloro-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amineand (2-methoxyphenyl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz) δ 7.74 (dd, J=1.8, 7.4 Hz, 1H), 7.56 (s,1H), 7.43 (s, 1H), 7.40-7.31 (m, 1H), 7.13-7.05 (m, 1H), 7.00 (d, J=8.0Hz, 1H), 6.94 (s, 1H), 4.82-4.72 (m, 1H), 4.53 (brs, 1H), 4.36 (d, J=4.8Hz, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 2.65 (s, 3H), 1.59 (d, J=6.8 Hz,6H). LC-MS (m/z) 391.1 (MH⁺); t_(R)=0.47 minutes (Method E).

Example 64:1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-phenyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5-chloro-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amineand phenylboronic acid.

¹H NMR (Chloroform-d 400 MHz) δ 8.00-7.99 (m, 2H), 7.58 (s, 1H),7.49-7.43 (m, 3H), 7.41-7.37 (m, 1H), 6.88 (s, 1H), 4.79-4.69 (m, 1H),4.56 (brs, 1H), 4.43 (d, J=4.8 Hz, 2H), 3.93 (s, 3H), 2.67 (s, 3H), 1.59(d, J=6.4 Hz, 6H). LC-MS (m/z) 361.3 (MH⁺); t_(R)=0.45 minutes (MethodE).

Example 65:1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(2-methyl-3-thienyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5-chloro-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amineand 4,4,5,5-tetramethyl-2-(2-methyl-3-thienyl)-1,3,2-dioxaborolane.

¹H NMR (Chloroform-d, 400 MHz) δ 7.55 (s, 1H), 7.40 (s, 1H), 7.26 (d,JJJ=4.8 Hz 1H), 7.08 (d, JJJ=5.2 Hz 1H), 6.60 (brs, 1H), 4.77-4.72 (m,1H), 4.57 (brs, 1H), 4.36 (d, J=4.4 Hz, 2H), 3.92 (s, 3H), 2.66 (s, 3H),2.62 (s, 3H), 1.58 (d, J=6.4 Hz, 6H)). LC-MS (m/z) 381.0 (MH⁺);t_(R)=2.06 minutes (Method F).

Example 66:5-(1,5-dimethylpyrazol-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5-chloro-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amineand1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole.

¹H NMR (DMSO-d₆, 400 MHz) δ 7.74 (s, 1H), 7.64 (s, 1H), 7.44 (s, 1H),6.57 (brs, 1H), 6.57 (s, 1H), 5.13-5.07 (m, 1H), 4.38 (d, J=5.2 Hz, 2H),3.76 (s, 3H), 3.75 (s, 3H), 2.56 (s, 3H), 2.41 (s, 3H), 1.42 (d, J=6.4Hz, 6H). LC-MS (m/z) 379.4 (MH⁺); t_(R)=0.38 minutes (Method E).

Example 67:5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 1, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2, (2-ethoxy-3-pyridyl)boronic acid and(1-methyl-1H-pyrazol-3-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27 (dd, J=1.6, 7.2 Hz, 1H), 8.17 (dd,J=1.6, 4.8 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.21 (s, 1H), 7.02 (dd,J=4.8, 7.6 Hz, 1H), 6.25 (d, J=2.0 Hz, 1H), 5.24 (brs, 1H), 4.65-4.60(m, 1H), 4.51-4.46 (m, 4H), 3.92 (s, 3H), 2.65 (s, 3H), 2.22-2.15 (m,1H), 1.92-1.85 (m, 1H), 1.62 (d, J=6.4 Hz, 3H), 1.43 (t, J=6.8 Hz, 3H),0.92 (t, J=7.6 Hz, 3H). LC-MS (m/z) 420.1 (MH⁺); t_(R)=1.87 (Method A).

Example 68:3-methyl-1-[1-methylpropyl]-N-[(2-methyltetrazol-5-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 1, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and (2-methyl-2H-tetrazol-5-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27 (dd, J=7.50, 1.98 Hz, 1H) 8.19(dd, J=5.07, 1.98 Hz, 1H) 7.25 (s, 1H) 7.03 (dd, J=7.39, 4.96 Hz, 1H)5.29 (s, 1H) 4.78 (d, J=5.07 Hz, 2H) 4.61-4.68 (m, 1H) 4.37-4.41 (m, 5H)2.66 (s, 3H) 2.18 (s, 1H) 1.80-1.96 (m, 3H) 1.65 (d, J=6.62 Hz, 3H) 1.06(t, J=7.39 Hz, 3H) 0.92 (t, J=7.39 Hz, 3H). LC-MS (m/z) 436.1 (MH⁺);t_(R)=1.97 (Method A).

Example 69:5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared using the same procedure as described for example 1, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1, (2-ethoxy-3-pyridyl)boronic acid and(1-methyl-1H-pyrazol-4-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.18-8.14 (m, 2H), 8.11 (s, 1H), 7.59(s, 1H), 7.40 (s, 1H), 7.11-7.07 (m, 2H), 6.73-6.72 (m, 1H), 5.01-4.96(m, 1H), 4.39-4.33 (m, 4H), 3.77 (s, 3H), 2.00-1.97 (m, 1H), 1.81-1.79(m, 1H), 1.49 (d, J=6.8 Hz, 3H), 1.25 (t, J=6.8 Hz, 3H), 0.73 (t, J=7.2Hz, 3H). SFC-MS: t_(R)=4.72 min, ee %=97.51. LC-MS (m/z) 406.1 (MH⁺);t_(R)=2.09 (Method A).

Example 70:5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 1, from1-(se-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2, (2-ethoxy-3-pyridyl)boronic acid and(1-methyl-1H-pyrazol-4-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.17-8.14 (m, 2H), 8.11 (s, 1H), 7.59(s, 1H), 7.40 (s, 1H), 7.11-7.06 (m, 2H), 6.74-6.71 (m, 1H), 5.01-4.97(m, 1H), 4.39-4.33 (m, 4H), 3.77 (s, 3H), 2.00-1.95 (m, 1H), 1.82-1.77(m, 1H), 1.49 (d, J=6.4 Hz, 3H), 1.25 (t, J=6.8 Hz, 3H), 0.73 (t, J=7.2Hz, 3H). SFC-MS: t_(R)=4.48 min, ee %=95.47. LC-MS (m/z) 406.1 (MH⁺);t_(R)=2.01 (Method A).

Example71:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine,2-ethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and(4-methylthiazol-5-yl)methanamine dihydrochloride.

¹H NMR (DMSO-de, 600 MHz) δ 8.84 (s, 1H), 8.17 (dd, J=4.9, 1.9 Hz, 1H),8.14-8.08 (m, 2H), 7.07 (dd, J=7.3, 4.7 Hz, 2H), 7.02 (s, 1H), 5.26(hept, J=6.4 Hz, 1H), 4.67 (d, J=5.3 Hz, 2H), 4.34 (q, J=7.0 Hz, 2H),2.44 (s, 3H), 1.50 (d, J=6.3 Hz, 6H), 1.21 (t, J=7.0 Hz, 3H). LC-MS(m/z) 409.5 (MH⁺); t_(R)=0.51 (Method D).

Example72:5-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]oxymethyl]-2-methyl-oxazole

Prepared using the same procedure as described for example 1, from5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine,2-ethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and(2-methyloxazol-5-yl)methanol.

¹H NMR (DMSO-de, 600 MHz) δ 8.24 (dd, J=4.9, 2.0 Hz, 1H), 8.18 (dd,J=7.3, 2.0 Hz, 1H), 7.65 (s, 1H), 7.28 (s, 1H), 7.14 (dd, J=7.4, 4.9 Hz,1H), 5.45 (s, 2H), 5.11 (hept, J=6.7 Hz, 1H), 4.45 (q, J=7.0 Hz, 2H),2.51 (s, 3H), 2.43 (s, 3H), 1.44 (d, J=6.6 Hz, 6H), 1.36 (t, J=7.0 Hz,3H). LC-MS (m/z) 408.6 (MH⁺); t_(R)=0.64 (Method D).

Example 73:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrimidin-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and pyrimidin-4-ylmethanamine.

¹H NMR (400 MHz, Chloroform-d) δ 9.28 (s, 1H), 8.76 (d, J=5.3 Hz, 1H),8.27 (brd, J=7.5 Hz, 1H), 8.19 (brd, J=3.3 Hz, 1H), 7.45 (brs, 1H), 7.11(s, 1H), 7.04 (dd, J=5.0, 6.9 Hz, 1H), 6.30 (weak br s, 1H), 5.11 (m,1H), 4.68 (m 2H), 4.46 (q, J=7.1 Hz, 2H), 2.68 (s, 3H), 1.72 (d, J=6.6Hz, 6H), 1.39 (t, J=7.1 Hz, 3H). LC-MS (m/z) 404.1 (MH⁺); t_(R)=1.89(Method C).

Example 74:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrimidin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and pyrimidin-2-ylmethanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.83 (d, J=4.8 Hz, 2H), 8.28 (dd,J=2.0, 7.2 Hz, 1H), 8.19 (dd, J=2.0, 4.8 Hz, 1H), 7.34-7.31 (m, 1H),7.19 (s, 1H), 7.03 (dd, J=5.2, 7.6 Hz, 1H), 6.45 (brs, 1H), 5.17-5.10(m, 1H), 4.74 (d, J=4.0 Hz, 2H), 4.50 (q, J=6.8 Hz, 2H), 2.67 (s, 3H),1.72 (d, J=6.4 Hz, 6H), 1.46 (t, J=6.8 Hz, 3H). LC-MS (m/z) 404 (MH⁺);t_(R)=2.20 (Method B).

Example 75:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methylpyrimidin-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and(4-methylpyrimidin-2-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.65 (d, J=5.2 Hz, 1H), 8.25 (dd,J=2.0, 7.2 Hz, 1H), 8.18 (dd, J=2.0, 5.2 Hz, 1H), 7.18-7.15 (m, 2H),7.03 (dd, J=5.2, 7.2 Hz, 1H), 6.57 (brs, 1H), 5.21-5.15 (m, 1H), 4.68(d, J=4.0 Hz, 2H), 4.50 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.61 (s, 3H),1.73 (d, J=6.4 Hz, 6H), 1.46 (t, J=7.2 Hz, 3H). LC-MS (m/z) 418.1 (MH⁺);t_(R)=2.2 (Method C).

Example 76:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrazin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and pyrazin-2-ylmethanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.73 (d, J=1.6 Hz, 1H), 8.63 (dd,J=2.4, 1.6 Hz, 1H), 8.59 (d, J=2.4 Hz, 1H), 8.26 (dd, J=2, 7.6 Hz, 1H),8.18 (dd, J=2, 4.8 Hz, 1H), 7.18 (s, 1H), 7.05-7.02 (m, 1H), 6.10 (brs,1H), 5.06-5.03 (m, 1H), 4.7 (d, J=4.0 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H),2.67 (s, 3H), 1.69 (d, J=6.4 Hz, 6H), 1.42 (t, J=7.2 Hz, 3H). LC-MS(m/z) 404.1 (MH⁺); t_(R)=2.19 (Method B).

Example 77:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and(2-(trifluoromethyl)pyridin-3-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.67-8.66 (m, 1H), 8.26-8.23 (m, 1H),8.16-8.13 (m, 1H), 7.99-7.98 (m, 1H), 7.52-7.49 (m, 1H), 7.06 (s, 1H),7.02-6.99 (m, 1H), 4.94-4.87 (m, 4H), 4.34-4.29 (m, 2H), 2.66 (s, 3H),1.66 (d, J=6.4 Hz, 6H), 1.17 (t, J=7.2 Hz, 3H). LC-MS (m/z) 471 (MH⁺);t_(R)=2.1 (Method A).

Example 78:4-[[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]amino]methyl]-1-methyl-pyridin-2-one

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and4-(aminomethyl)-1-methylpyridin-2(1H)-one.

¹H NMR (Chloroform-d, 400 MHz) δ 8.23 (dd, J=1.6, 5.6 Hz, 1H), 8.16 (dd,J=2.0, 5.2 Hz, 1H), 7.29 (d, J=6.8 Hz, 1H), 7.04-7.01 (m, 2H), 6.61 (s,1H), 6.21 (d, J=6.8 Hz, 1H), 4.89 (m, 1H), 4.44-4.39 (m, 4H), 3.54 (s,3H), 2.65 (s, 3H), 1.66 (d, J=6.4 Hz, 6H), 1.33 (t, J=7.2 Hz, 3H). LC-MS(m/z) 433.1 (MH⁺); t_(R)=1.88 (Method B).

Example 79:5-(2-(ethylamino)pyridin-3-yl)-1-isopropyl-3-methyl-N-((1-methyl-H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineandN-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine.

¹H NMR (Chloroform-d, 600 MHz) δ 69.34-9.27 (m, 1H), 8.16 (dd, J=4.9,1.8 Hz, 1H), 7.77 (dd, J=7.6, 1.8 Hz, 1H), 7.57 (s, 1H), 7.42 (s, 1H),6.80 (s, 1H), 6.58 (dd, J=7.5, 4.9 Hz, 1H), 4.72 (hept, J=6.6 Hz, 1H),4.57 (t, J=5.0 Hz, 1H), 4.41 (d, J=4.7 Hz, 2H), 3.93 (s, 3H), 3.57 (qd,J=7.2, 4.6 Hz, 2H), 2.61 (s, 3H), 1.59 (d, J=6.5 Hz, 6H), 1.37 (t, J=7.2Hz, 3H). LC-MS (m/z) 405.6 (MH⁺); t_(R)=0.45 minutes (Method D)

Example 81:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (4-methoxypyridin-2-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.45 (d, J=2.4 Hz, 1H), 8.26 (d, J=7.2Hz, 1H), 8.18 (d, J=4.4 Hz, 1H), 7.12 (s, 1H), 7.03 (dd, J=5.2, 6.8 Hz,1H), 6.87-6.81 (m, 2H), 6.54-6.49 (m, 1H), 5.13-5.06 (m, 1H), 4.57-4.55(m, 2H), 4.50-4.45 (m, 2H), 3.89 (s, 3H), 2.67 (s, 3H), 1.69 (d, J=6.4Hz, 6H), 1.42 (t, J=1.6 Hz, 3H). LC-MS (m/z) 433.1 (MH⁺); t_(R)=2.32(Method B).

Example 82:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxypyrazin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (6-methoxypyrazin-2-yl)methanaminehydrochloride.

¹H NMR (Chloroform-d, 400 MHz) δ 8.25-8.27 (m, 2H), 8.23 (s, 1H),8.18-8.19 (m, 1H), 7.21 (s, 1H), 7.03 (dd, J=5.2, 7.6 Hz 1H), 5.72-5.74(m, 1H), 4.99-5.06 (s, 1H), 4.60 (d, J=4.4 Hz 2H), 4.45-4.51 (m, 2H),4.03 (s, 3H), 2.66 (s, 3H), 1.67 (d, J=6.4 Hz, 6H), 1.42 (t, J=7.0 Hz,3H). LC-MS (m/z) 434.1 (MH⁺); t_(R)=1.86 (Method A).

Example 83:5-(2-ethoxy-3-pyridyl)-N-[(5-fluoropyrimidin-2-yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and(5-fluoropyrimidin-2-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.70 (s, 2H), 8.27 (dd, J=2.0, 6.0 Hz,1H), 8.20 (d, J=2.8 Hz, 1H), 7.18 (s, 1H), 7.04 (dd, J=4.8, 7.2 Hz, 1H),6.25 (brs, 1H), 5.13-5.06 (m, 1H), 4.75 (d, J=4.4 Hz, 2H), 4.50 (q J=7.2Hz, 2H), 3.69 (s, 3H), 1.71 (d, J=6.8 Hz, 6H), 1.46 (t, J=7.2 Hz, 3H)LC-MS (m/z) 422.1 (MH⁺); t_(R)=2.2 (Method C).

Example 84:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (2-methylpyridin-3-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): β=8.50 (d, J=5.2 Hz, 1H), 8.26 (d, J=7.2Hz, 1H), 8.16 (d, J=5.2 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.19-7.16 (m,1H), 7.14 (s, 1H), 7.03-7.00 (m, 1H), 4.83-4.78 (m, 1H), 4.68 (brs, 1H),4.54 (d, J=5.2 Hz, 2H), 4.36 (q, J=7.2 Hz, 2H), 2.66 (s, 6H), 1.62 (d,J=6.4 Hz, 6H), 1.25 (t, J=6.8 Hz, 3H) LC-MS (m/z) 417.1 (MH⁺);t_(R)=1.33 (Method A).

Example 85:5-(2-ethoxy-3-pyridyl)-N-[(2-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (2-fluoropyridin-3-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26-8.14 (m, 1H), 8.19-8.15 (m, 2H),7.90-7.80 (m, 1H), 7.22-7.19 (m, 1H), 7.13 (s, 1H), 7.03-7.00 (m, 1H),5.00-4.80 (m, 2H), 4.67-4.66 (m, 2H), 4.37 (q, J=7.2 Hz, 2H), 2.65 (s,3H), 1.65 (d, J=6.8 Hz, 6H), 1.33 (t, J=7.2 Hz, 3H) LC-MS (m/z) 421.1(MH⁺); t_(R)=1.8 (Method A).

Example 86:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (2-methoxypyridin-3-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26-8.23 (m, 1H), 8.16-8.13 (m, 2H),7.62-7.61 (m, 1H), 7.15 (s, 1H), 7.03-7.00 (m, 1H), 6.92-6.89 (m, 1H),5.13-5.11 (m, 1H), 4.93-4.90 (m, 1H), 4.53-4.52 (m, 2H), 4.41 (q, J=7.2Hz, 2H), 4.04 (s, 3H), 2.65 (s, 3H), 1.65 (d, J=6.8 Hz, 6H), 1.33 (t,J=7.2 Hz, 3H Chloroform-d, 400 MHz). LC-MS (m/z) 433 (MH⁺); t_(R)=2.04(Method A).

Example 87:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(6-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (6-methylpyridin-3-yl)methanamine¹H NMR (Chloroform-d, 400 MHz): β=8.60 (s, 1H), 8.25 (brd, J=7.7 Hz,1H), 8.17 (brd, J=4.6 Hz, 1H), 7.66 (brd, J=8.4 Hz, 1H), 7.20-7.17 (m,1H), 7.20 (brd, J=11.5 Hz, 1H), 7.06-6.99 (m, 1H), 4.82 (s, 1H), 4.71(s, 1H), 4.55 (br s, 2H), 4.42 (q, J=7.1 Hz, 2H), 2.65 (s, 3H), 2.59 (s,3H), 1.62 (d, J=6.4 Hz, 6H), 1.33 (t, J=7.1 Hz, 3H). LC-MS (m/z) 417.1(MH⁺); t_(R)=1.36 (Method A).

Example 88:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2-methoxyphenyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (2-methoxyphenyl)methanamine.

¹H NMR (400 MHz, Chloroform-d) δ=8.24 (d, J=7.3 Hz, 1H), 8.18-8.13 (m,1H), 7.37-7.30 (m, 2H), 7.23 (s, 1H), 7.03-6.94 (m, 3H), 5.08 (brs, 1H),4.89-4.81 (m, 1H), 4.53 (d, J=5.3 Hz, 2H), 4.45 (q, J=6.9 Hz, 2H), 3.90(s, 3H), 2.64 (s, 3H), 1.62 (d, J=6.6 Hz, 6H), 1.38 (t, J=7.1 Hz, 3H).LC-MS (m/z) 432.1 (MH⁺); t_(R)=2.19 (Method A).

Example 89:5-(2-ethoxy-3-pyridyl)-N-[(2-fluorophenyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (2-fluorophenyl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): β=8.26-8.24 (m, 1H), 8.18-8.17 (m, 1H),7.44 (br s, J=7.7 Hz, 1H), 7.34-7.32 (m, 1H), 7.20 (s, 1H), 7.18-7.14(m, 2H), 7.03-7.02 (m, 1H), 4.89-4.85 (m, 2H), 4.65-4.64 (m, 2H), 4.42(q, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.64 (d, J=6.4 Hz, 6H), 1.33 (t, J=6.8Hz, 3H). LC-MS (m/z) 420 (MH⁺); t_(R)=2.14 (Method A)

Example 90:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[2-(trifluoromethyl)phenyl]methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and(2-(trifluoromethyl)phenyl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.34-8.22 (m, 1H), 8.17-8.15 (m, 1H),7.75 (d, J=7.6 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.55 (t, J=6.4 Hz, 1H),7.45 (t, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.03-6.99 (m, 1H), 4.91-4.86 (m,1H), 4.82 (br s, 2H), 4.35 (q, J=7.2 Hz, 2H), 2.66 (s, 3H), 1.62 (d,J=6.4 Hz, 6H), 1.23 (t, J=6.8 Hz, 3H). LC-MS (m/z) 470 (MH⁺); t_(R)=1.87(Method 1)

Example 91:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methoxypyrazin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (3-methoxypyrazin-2-yl)methanaminehydrochloride.

¹H NMR (Chloroform-d, 400 MHz): δ 8.34-8.32 (m, 1H), 8.20-8.12 (m, 3H),7.30 (s, 1H), 7.04 (dd, J=7.6, 4.8 Hz, 1H), 6.53 (brs, 1H), 5.14-5.08(m, 1H), 4.58 (d, J=4.0 Hz 2H), 4.52 (q, J=7.2 Hz, 2H), 4.08 (s, 3H),2.67 (s, 3H), 1.71 (d, J=6.8 Hz, 6H), 1.51 (t, J=7.2 Hz, 3H). LC-MS(m/z) 434.1 (MH⁺); t_(R)=2.01 (Method A).

Example92:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (4-methoxy-3-pyridyl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 6=8.53-8.50 (m, 2H), 8.24 (dd, J=1.6,7.2 Hz, 1H), 8.17 (dd, J=2.8, 4.8 Hz, 1H), 7.23 (s, 1H), 7.05-7.00 (m,1H), 6.89 (d, J=6.0 Hz, 1H), 4.95 (brs, 1H), 4.87-4.81 (m, 1H), 4.54 (d,J=6.4 Hz, 2H), 4.47 (q, J=7.8 Hz, 2H), 3.95 (s, 3H), 2.65 (s, 3H), 1.62(d, J=6.4 Hz, 6H), 1.39 (t, J=7.8 Hz, 3H). LC-MS (m/z) 433.1 (MH⁺);t_(R)=1.39 (Method A).

Example 93:1-isopropyl-3-methyl-N-[(2-methyltetrazol-5-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-propoxy-3-pyridyl)boronic acid and(2-methyl-2H-tetrazol-5-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): β=8.26-8.19 (m, 2H), 7.22 (s, 1H),7.06-7.03 (m, 1H), 5.48 (br. s, 1H), 4.99-4.91 (m, 1H), 4.81 (d, J=3.2Hz, 2H), 4.41-4.38 (m, 5H), 2.65 (s, 3H), 1.88-1.82 (m, 2H), 1.67 (d,J=6.4 Hz, 6H) 1.06 (t, J=7.2 Hz, 3H). LC-MS (m/z) 422.1 (MH⁺);t_(R)=2.04 (Method C).

Example 94:1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,2-propoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and(1-methyl-1H-pyrazol-4-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26 (dd, J=2.0, 7.6 Hz, 1H), 8.18(dd, J=0.0, 5.2 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 1H), 7.22 (s, 1H), 7.03(dd, J=4.8, 7.2 Hz, 1H), 4.84-4.67 (m, 1H), 4.48 (brs, 1H), 4.40-4.33(m, 4H), 3.94 (s, 3H), 2.65 (s, 3H), 1.89-1.74 (m, 2H), 1.59 (d, J=6.8Hz, 6H), 1.03 (t, J=7.6 Hz, 3H). LC-MS (m/z) 420.4 (MH⁺); t_(R)=0.59(Method D).

Example 95:1-isopropyl-5-(2-methoxy-3-pyridyl)-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-methoxypyridin-3-yl)boronic acid and(2-methoxypyridin-3-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.20-8.18 (m, 1H), 8.16-8.14 (m, 2H),7.64-7.62 (m, 1H), 7.04-7.03 (m, 1H), 6.97 (s, 1H), 6.93-6.92 (m, 1H),5.24-5.21 (m, 1H), 4.93-4.87 (m, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.04 (s,3H), 3.89 (s, 3H), 2.64 (s, 3H), 1.65 (d, J=6.4 Hz, 6H). LC-MS (m/z)419.1 (MH⁺); t_(R)=1.82 (Method A).

Example 96:1-isopropyl-5-(2-methoxy-3-pyridyl)-N-[(6-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-methoxypyridin-3-yl)boronic acid and (6-methoxy-3-pyridyl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26 (d, J=1.6 Hz, 1H), 8.16-8.21 (m,2H), 7.67 (dd, J=2.4, 8.4 Hz, 1H), 7.02-7.07 (m 2H), 6.80 (d, J=8.8 Hz,1H), 4.76-4.82 (m, 1H), 4.69 (brs, 1H), 4.47 (d, J=5.2 Hz, 2H), 3.96 (s,3H), 3.94 (s, 3H), 2.65 (s, 3H), 1.61 (d, J=6.4 Hz, 6H). LC-MS (m/z) 419(MH⁺); t_(R)=1.83 (Method A).

Example 97:5-(2-isopropoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-isopropoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-methyl-1H-pyrazole-4-carbaldehyde.

¹H NMR (600 MHz, DMSO) δ 8.21-8.09 (m, 2H), 7.58 (d, J=9.7 Hz, 1H), 7.38(s, 1H), 7.08 (s, 1H), 7.06 (dd, J=7.3, 4.9 Hz, 1H), 6.67 (t, J=5.5 Hz,1H), 5.44-5.33 (m, 1H), 5.16 (dt, J=12.7, 6.4 Hz, 1H), 4.36 (d, J=5.5Hz, 2H), 3.76 (s, 3H), 2.46 (s, 3H), 1.45 (d, J=6.4 Hz, 6H), 1.23 (d,J=6.2 Hz, 6H). LC-MS (m/z) 420.4 (MH⁺); t_(R)=0.52 (Method E).

Example 98:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.21-8.17 (m, 2H), 8.12 (s, 1H), 7.15(s, 1H), 7.02-6.99 (m, 1H), 5.60 (brs, 1H), 4.99-4.93 (m, 1H), 4.65 (s2H), 4.46 (q, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.65 (d, J=6.4 Hz, 6H), 1.39(t, J=7.2 Hz, 3H). LC-MS (m/z) 393.1 (MH⁺); t_(R)=2.3 (Method C).

Example 99:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(2H-tetrazol-5-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2H-tetrazole-5-carbaldehyde.

¹H NMR (DMSO-d₆ 400 MHz): δ 8.17-8.13 (m, 2H), 7.09-7.05 (m, 1H), 6.99(s, 1H), 6.91 (br. s, 1H), 5.20-5.14 (m, 1H), 4.79 (d, J=5.2 Hz, 2H),4.30 (q, J=6.8 Hz, 2H), 2.47 (s, 3H), 1.49 (d, J=6.4 Hz, 6H), 1.22 (t,J=6.8 Hz, 3H). LC-MS (m/z) 394 (MH⁺); t_(R)=1.77 (Method C).

Example 100:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand picolinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.66-8.64 (m, 1H), 8.26 (dd, J=2.0,7.2 Hz, 1H), 8.18 (dd, J=2.0, 4.8 Hz, 1H), 7.77-7.72 (m, 1H), 7.38-7.36(m, 1H), 7.30-7.28 (m, 1H), 7.14 (s, 1H), 7.03 (dd, J=4.8, 7.2 Hz, 1H),6.53 (brs, 1H), 5.15-5.08 (m, 1H), 4.62 (d, J=4.0 Hz, 2H), 4.48 (q,J=6.8 Hz, 2H), 2.67 (s, 3H), 1.70 (d, J=6.8 Hz, 6H), 1.42 (t, J=7.2 Hz,3H). LC-MS (m/z) 403.1 (MH⁺); t_(R)=2.15 (Method A).

Example 101:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(6-methyl-2-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-methylpicolinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.27-8.26 (m, 1H), 8.19-8.18 (m, 1H),7.66-7.62 (m, 1H), 7.18-7.14 (m, 2H), 7.11 (s, 1H), 7.04 (dd, J=4.8, 7.2Hz, 1H), 6.84 (brs, 1H), 5.22-5.19 (m, 1H), 4.57 (d, J=3.6 Hz, 2H), 4.49(q, J=6.8 Hz, 2H), 2.68 (s, 3H), 2.61 (s, 3H), 1.73 (d, J=6.4 Hz, 6H),1.43 (t, J=7.2 Hz, 3H). LC-MS (m/z) 417.1 (MH⁺); t_(R)=2.04 (Method A).

Example 102:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-methoxypicolinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.28-8.26 (m, 1H), 8.19-8.18 (m, 1H),7.65-7.61 (m, 1H), 7.17 (s, 1H), 7.05-7.02 (m, 1H), 6.96-6.94 (m, 1H),6.75-6.72 (m, 1H), 6.17 (brs, 1H), 5.11-5.08 (m, 1H), 4.55-4.46 (m, 4H),4.01 (s, 3H), 2.67 (s, 3H), 1.66 (d, J=6.0 Hz, 6H), 1.43 (t, J=7.2 Hz,3H). LC-MS (m/z) 433.1 (MH⁺); t_(R)=2.47 (Method A).

Example 103:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-4-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-methylisonicotinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.50 (d, J=5.2 Hz, 1H), 8.22 (dd,J=2.0, 7.2 Hz, 1H), 8.15 (dd, J=2.0, 4.2 Hz, 1H), 7.20 (s, 1H), 7.15 (d,J=5.2 Hz, 1H), 7.03 (s, 1H), 7.00 (dd, J=5.2, 7.6 Hz, 1H), 4.91-4.86 (m,2H), 4.57 (d, J=5.2 Hz, 2H), 4.32 (q, J=7.2 Hz, 2H), 2.66 (s, 3H), 2.57(s, 3H), 1.67 (d, J=6.4 Hz, 6H), 1.21 (t, J=7.2 Hz, 3H). LC-MS (m/z)417.1 (MH⁺); t_(R)=1.53 (Method A).

Example 104:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2-methoxy-4-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-methoxyisonicotinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.22 (d, J=7.6 Hz, 1H), 8.18-8.14 (m,2H), 7.04 (s, 1H), 7 (dd, J=5.2, 7.6 Hz 1H), 6.92 (d, J=5.2 Hz 1H), 6.79(s, 1H), 4.89-4.86 (m, 2H), 4.56 (d, J=5.2 Hz, 2H), 4.34 (q, J=7.2 Hz,2H), 3.94 (s, 3H), 2.66 (s, 3H), 1.66 (d, J=6.8 Hz, 6H), 1.24 (t, J=7.2Hz, 3H). LC-MS (m/z) 433.1 (MH⁺); t_(R)=1.94 (Method A).

Example 105:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-methylpyrimidine-4-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.65 (d, J=5.2 Hz, 1H), 8.26 (dd,J=2.0, 7.6 Hz, 1H), 8.18 (dd, J=2.0, 7.6 Hz, 1H), 7.20 (d, J=5.2 Hz,1H), 7.09 (s, 1H), 7.05-7.02 (m, 1H), 6.45 (brs, 1H), 5.16-5.13 (m, 1H),4.59 (d, J=4.0 Hz, 2H), 4.46 (q, J=7.2 Hz, 2H), 2.81 (s, 3H), 2.67 (s,3H), 1.73 (d, J=6.4 Hz, 6H), 1.40 (t, J=7.2 Hz, 3H). LC-MS (m/z) 418.1(MH⁺); t_(R)=1.96 (Method C)

Example 106:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-methoxynicotinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.24 (s, 1H), 8.19-8.18 (m, 1H),8.14-8.12 (m, 2H), 7.38 (s, 1H), 7.10-7.03 (m, 1H), 7.02-6.97 (m, 1H),6.94 (s, 1H), 5.27-5.21 (m, 1H), 4.58 (d, J=4.8 Hz, 2H), 4.24 (q, J=7.2Hz, 2H), 3.78 (s, 3H), 2.46 (s, 3H), 1.48 (d, J=6.0 Hz, 6H), 1.10 (t,J=6.8 Hz, 3H). LC-MS (m/z) 433.1 (MH⁺); t_(R)=1.63 (Method A).

Example 107:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[6-(trifluoromethyl)-2-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-(trifluoromethyl)picolinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.27 (dd, J=2.0, 7.2 Hz, 1H), 8.18(dd, J=4.8, 2.0 Hz 1H), 8.00-7.95 (m, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.59(d, J=7.6 Hz, 1H), 7.13 (s, 1H), 7.04 (dd, J=7.2, 4.8 Hz, 1H), 6.68(brs, 1H), 5.19-5.16 (m, 1H), 4.70 (d, J=3.6 Hz, 2H), 4.49 (q, J=7.2 Hz,2H), 2.67 (s, 3H), 1.71 (d, J=6.4 Hz, 6H), 1.44 (t, J=7.2 Hz, 3H). LC-MS(m/z) 471 (MH⁺); t_(R)=2.34 (Method A).

Example 108:3-[[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]amino]methyl]-1-methyl-pyridin-2-one

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.31-8.24 (m, 1H), 8.19-8.17 (m, 1H),7.50-7.42 (m, 1H), 7.30-7.28 (m, 1H), 7.15 (s, 1H), 7.05-7.02 (m, 1H),6.21-6.17 (m, 1H), 5.06-4.95 (m, 1H), 4.51-4.45 (m, 4H), 3.59 (s, 3H),2.65 (s, 3H), 1.64 (d, J=6.8 Hz, 6H), 1.40 (t, J=7.2 Hz, 3H). LC-MS(m/z) 433 (MH⁺); t_(R)=1.93 (Method C).

Example 109:5-(2-ethoxy-3-pyridyl)-N-[(1-ethylpyrazol-4-yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-ethyl-1H-pyrazole-4-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.28 (dd, J=7.6, 2.0 Hz, 1H), 8.18(dd, J=4.8, 1.6 Hz, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 7.25 (s, 1H), 7.03(dd, J=7.6, 5.2 Hz, 1H), 4.77-4.50 (m, 1H), 4.52-4.45 (m, 3H), 4.39 (d,J=4.8 Hz, 2H), 4.2 (q, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.59 (d, J=6.8 Hz,6H), 1.52 (t, J=7.2 Hz, 3H), 1.40 (t, J=6.8 Hz, 3H). LC-MS (m/z) 420.1(MH⁺); t_(R)=2.13 (Method F).

Example 110:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-propylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-propyl-1H-pyrazole-4-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.27 (dd, J=2.0, 7.2 Hz, 1H), 8.18(dd, J=2.0, 5.2 Hz, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 7.24 (s, 1H), 7.03(dd, J=4.8, 7.2 Hz, 1H), 4.77-4.74 (m, 1H), 4.48 (q, J=7.2 Hz, 3H), 4.39(d, J=4.4 Hz, 2H), 4.09 (t, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.94-1.88 (m,2H), 1.59 (d, J=6.4 Hz, 6H), 1.4 (t, J=6.8 Hz, 3H), 0.93 (t, J=7.2 Hz,3H). LC-MS (m/z) 434.1 (MH⁺); t_(R)=1.89 (Method A).

Example 111:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-methoxynicotinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.30-8.24 (m, 2H), 8.20-8.15 (m, 1H),7.67 (d, J=8.0 Hz, 1H), 7.21 (s, 1H), 7.04-7.01 (m, 1H), 6.80 (d, J=8.0Hz, 1H), 4.80 (dd, J=4.8, 6.4 Hz, 1H), 4.65 (brs, 1H), 4.49-4.42 (m,4H), 3.96 (s, 3H), 2.66 (s, 3H), 1.59 (d, J=4.8 Hz, 6H), 1.40-1.34 (m,3H). LC-MS (m/z) 433.1 (MH⁺); t_(R)=2.33 (Method F).

Example 112:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-methoxypicolinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.33 (d, J=1.6 Hz, 1H), 8.26 (dd,J=2.0, 7.6 Hz, 1H), 8.18 (dd, J=2.0, 4.8 Hz, 1H), 7.31-7.28 (m, 2H),7.13 (s, 1H), 7.03 (dd, J=7.2, 7.6 Hz, 1H), 6.36 (s, 1H), 5.11-5.05 (m,1H), 4.56 (d, J=4.4 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H), 3.91 (s, 3H), 2.66(s, 3H), 1.69 (d, J=7.2 Hz, 6H), 1.42 (t, J=7.2 Hz, 3H). LC-MS (m/z)433.1 (MH⁺); t_(R)=2.14 (Method A).

Example 113:5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methylthiazol-4-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1, from5,7-dibromo-3-methyl-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (2-methylthiazol-4-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.26 (dd, J=1.6, 7.2 Hz 1H), 8.18 (dd,J=2.0, 4.8 Hz 1H), 7.24 (s, 1H), 7.05-7.02 (m, 2H), 5.94-5.85 (m, 2H),5.28-5.25 (m, 2H), 5.20-5.16 (m, 2H), 4.57 (d, J=5.2 Hz, 2H), 4.46 (q,J=7.2 Hz, 2H), 2.76 (s, 3H), 2.66 (s, 3H), 1.39 (t, J=7.2 Hz, 3H). LC-MS(m/z) 437.4 (MH⁺); t_(R)=0.46 minutes (Method E).

Example 114:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxypyrazin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-methoxypyrazine-2-carbaldehyde.

¹H NMR (400 MHz, Chloroform-d): δ 8.24-8.28 (m, 2H), 8.16-8.23 (m, 2H),7.18 (s, 1H), 7.04 (brt, J=5.84 Hz, 1H), 5.80 (brs, 1H), 4.93-5.06 (m,1H), 4.60 (brd, J=3.75 Hz, 2H), 4.48 (q, J=6.69 Hz, 2H), 4.00 (s, 3H),2.66 (s, 3H), 1.66 (brd, J=6.39 Hz, 6H), 1.41 (t, J=6.95 Hz, 3H). LC-MS(m/z) 434.1 (MH⁺); t_(R)=1.99 (Method A).

Example 115:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(3-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand nicotinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): β=8.73 (s, 1H), 8.61 (d, J=3.6 Hz, 1H),8.24 (d, J=6.0 Hz, 1H), 8.16 (dd, J=1.6, 4.4 Hz, 1H), 7.76 (d, J=8.4 Hz,1H), 7.36-7.33 (m, 1H), 7.18 (s, 1H), 7.01 (dd, J=4.8, 7.6 Hz, 1H), 4.82(s, 1H), 4.75 (s, 1H), 4.60 (d, J=5.2 Hz, 2H), 4.40 (q, J=6.8 Hz, 2H),2.65 (s, 3H), 1.62 (d, J=6.4 Hz, 6H), 1.30 (t, J=7.2 Hz, 3H). LC-MS(m/z) 403.1 (MH⁺); t_(R)=1.41 (Method A).

Example 116:5-(2-ethoxy-3-pyridyl)-N-[(6-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-fluoronicotinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.33 (s, 1H), 8.26-8.24 (m, 1H),8.18-8.17 (m, 1H), 7.88-7.86 (m, 1H), 7.17 (s, 1H), 7.04-6.98 (m, 2H),4.83-4.82 (m, 1H), 4.74-4.72 (m, 1H), 4.59-4.58 (m, 2H), 4.41 (q, J=6.8Hz, 2H), 2.66 (s, 3H), 1.63 (d, J=6.8 Hz, 6H), 1.31 (t, J=6.8 Hz, 3H).LC-MS (m/z) 421 (MH⁺); t_(R)=1.89 (Method A).

Example 117:N-[[6-(difluoromethyl)-3-pyridyl]methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-(difluoromethyl)nicotinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.76 (s, 1H), 8.24 (dd, J=7.2, 2.0 Hz,1H), 8.16 (dd, J=5.2, 2.0 Hz, 1H), 7.92 (d, J=8.0, 1H), 7.68 (d, J=8.2Hz, 1H), 7.13 (s, 1H), 7.01 (dd, J=7.2, 4.8 Hz, 1H), 6.67 (t, J=55.2 Hz,1H), 4.87-4.83 (m, 2H), 4.68 (d, J=5.2 Hz, 2H), 4.35 (q, J=6.8 Hz, 2H),2.66 (s, 3H), 1.65 (d, J=6.8 Hz, 6H), 1.24 (t, J=7.2 Hz, 3H). LC-MS(m/z) 453.1 (MH⁺); t_(R)=1.92 (Method A).

Example 118:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 3-methoxypicolinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.33 (dd, J=2.0, 7.2 Hz, 1H), 8.23(dd, J=1.2, 4.8 Hz, 1H), 8.19 (dd, J=2.0, 5.2 Hz, 1H), 7.28-7.30 (m,2H), 7.22-7.24 (m, 1H), 7.04 (dd, J=4.8, 7.2 Hz, 1H), 6.96 (brs, 1H),5.12-5.21 (m, 1H), 4.57 (d, J=4.0 Hz, 2H), 4.52 (q, J=6.8 Hz, 2H), 3.94(s, 3H), 2.68 (s, 3H), 1.72 (d, J=6.4 Hz, 6H), 1.51 (t, J=7.0 Hz, 3H).LC-MS (m/z) 433.1 (MH⁺); t_(R)=2.08 (Method A).

Example 119:5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 and 1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26 (dd, J=2.0, 7.6 Hz, 1H), 8.18(dd, J=2.0, 4.2 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.22 (s, 1H), 7.03 (dd,J=4.8, 7.2 Hz, 1H), 6.36 (d, J=2.4 Hz, 1H), 5.29 (br. s, 1H), 4.64-4.60(m, 1H), 4.57 (d, J=4.8 Hz, 2H), 4.48 (q, J=6.8 Hz, 2H), 2.66 (s, 3H),2.22-2.14 (m, 1H), 1.90-1.85 (m, 1H), 1.61 (d, J=6.4 Hz, 3H), 1.43 (t,J=6.8 Hz, 3H), 0.89 (t, J=7.6 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺);t_(R)=2.25 (Method A).

Example 120:5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26 (dd, J=2.0, 7.2 Hz, 1H), 8.18(dd, J=2.0, 4.2 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.22 (s, 1H), 7.03 (dd,J=4.8, 7.2 Hz, 1H), 6.36 (d, J=2.4 Hz, 1H), 5.28 (br. s, 1H), 4.64-4.60(m, 1H), 4.57 (d, J=4.8 Hz, 2H), 4.48 (q, J=6.8 Hz, 2H), 2.66 (s, 3H),2.22-2.14 (m, 1H), 1.92-1.86 (m, 1H), 1.62 (d, J=6.8 Hz, 3H), 1.43 (t,J=6.8 Hz, 3H), 0.89 (t, J=7.2 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺);t_(R)=2.22 (Method A).

Example 121:5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 and 1-methyl-1H-1,2,4-triazole-3-carbaldehyde

¹H NMR (Chloroform-d, 400 MHz): δ 8.27 (dd, J=2.0, 7.2 Hz, 1H), 8.18(dd, J=2.0, 5.2 Hz, 1H), 8.05 (s, 1H), 7.20 (s, 1H), 7.03 (dd, J=4.8,7.2 Hz, 1H), 5.49 (br. s, 1H), 4.69-4.65 (m, 1H), 4.57 (d, J=4.8 Hz,2H), 4.49 (q, J=6.8 Hz, 2H), 3.95 (s, 3H), 2.66 (s, 3H), 2.21-2.16 (m,1H), 1.94-1.91 (m, 1H), 1.64 (d, J=6.4 Hz, 3H), 1.45 (t, J=7.2 Hz, 3H),0.93 (t, J=7.2 Hz, 3H). LC-MS (m/z) 421.1 (MH⁺); t_(R)=2.26 (Method C).

Example 122:5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1-methyl-1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26 (dd, J=2.0, 7.2 Hz, 1H), 8.18(dd, J=2.0, 5.2 Hz, 1H), 8.05 (s, 1H), 7.21 (s, 1H), 7.03 (dd, J=4.8,7.2 Hz, 1H), 5.49 (br. s, 1H), 4.68-4.65 (m, 1H), 4.57 (d, J=4.8 Hz,2H), 4.49 (q, J=6.8 Hz, 2H), 3.95 (s, 3H), 2.65 (s, 3H), 2.21-2.16 (m,1H), 1.94-1.89 (m, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.45 (t, J=6.8 Hz, 3H),0.93 (t, J=7.6 Hz, 3H). LC-MS (m/z) 421.1 (MH⁺); t_(R)=2.29 (Method C).

Example 123:5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 and 5-methyl-1,3,4-oxadiazole-2-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.30-8.28 (m, 1H), 8.21-8.20 (m, 1H),7.25 (s, 1H), 7.06-7.01 (m, 1H), 5.28-5.20 (m, 1H), 4.76-4.64 (m, 3H),4.51 (q, J=7.2 Hz, 2H), 2.66 (s, 3H), 2.58 (s, 3H), 2.23-2.18 (m, 1H),1.94-1.91 (m, 1H), 1.65 (d, J=6.4 Hz, 3H), 1.45 (t, J=6.8 Hz, 3H), 0.91(t, J=7.2 Hz, 3H). LC-MS (m/z) 422.1 (MH⁺); t_(R)=2.22 (Method C).

Example 124:5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 5-methyl-1,3,4-oxadiazole-2-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.30-8.28 (m, 1H), 8.20-8.19 (m, 1H),7.25 (s, 1H), 7.06-7.02 (m, 1H), 5.20-5.18 (m, 1H), 4.73-4.71 (m 2H),4.63-4.61 (m, 1H), 4.51 (q, J=7.2 Hz, 2H), 2.66 (s, 3H), 2.58 (s, 3H),2.23-2.16 (m, 1H), 1.94-1.90 (m, 1H), 1.65 (d, J=6.4 Hz, 3H), 1.44 (t,J=6.8 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H). LC-MS (m/z) 422.1 (MH⁺);t_(R)=2.17 (Method C).

Example 125:5-(2-ethoxy-3-pyridyl)-N-[(5-methoxy-3-pyridyl)methyl]-3-methyl-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 5-methoxynicotinaldehyde.

¹H NMR (DMSO-d₆ 400 MHz): β=8.21 (s, 1H), 8.16 (d, J=2.8 Hz, 1H), 8.13(s, 1H), 8.12-8.09 (m, 1H), 7.33-7.32 (m, 1H), 7.05-7.02 (m, 1H), 6.93(s, 1H), 6.91 (s, 1H), 4.96-4.93 (m, 1H), 4.57-4.56 (m, 2H), 4.25-4.20(m, 2H), 3.75 (s, 3H), 2.44 (s, 3H), 1.98-1.74 (m, 2H), 1.48 (d, J=6.4Hz, 3H), 1.08 (t, J=7.0 Hz, 3H), 0.73 (t, J=7.6 Hz, 3H). LC-MS (m/z)447.1 (MH⁺); t_(R)=1.62 (Method A).

Example 126:5-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-3-methyl-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 2-methoxyisonicotinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): β=8.24 (dd, J=2.0, 7.6 Hz, 1H), 8.17 (d,J=5.6 Hz, 1H), 8.15 (dd, J=1.6, 4.8 Hz, 1H), 7.07 (s, 1H), 7.00 (dd,J=5.2, 7.6 Hz, 1H), 6.91 (d, J=4.0 Hz, 1H), 6.78 (s, 1H), 4.80 (brs,1H), 4.55 (d, J=5.6 Hz, 3H), 4.35 (q, J=6.8 Hz, 2H), 3.94 (s, 3H), 2.66(s, 3H), 2.26-2.15 (m, 1H), 1.95-1.85 (m, 1H), 1.64 (d, J=6.4 Hz, 3H),1.25 (t, J=6.8 Hz, 3H), 0.90 (t, J=7.6 Hz, 3H). LC-MS (m/z) 447.1 (MH⁺);t_(R)=1.96 (Method A).

Example 127:5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 2-methyl-2H-tetrazole-5-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.28 (dd, J=7.6, 2.0 Hz, 1H), 8.18(dd, J=5.2, 2.0 Hz, 1H), 7.27 (s, 1H), 7.05-7.02 (m, 1H), 5.31-5.28 (m,1H), 4.79 (d, J=5.2 Hz, 2H), 4.67-4.62 (m, 1H), 4.50 (q, J=6.8 Hz, 2H),4.39 (s, 3H), 2.67 (s, 3H), 2.24-2.17 (m, 1H), 1.95-1.88 (m, 1H), 1.65(d, J=6.8 Hz, 3H), 1.45 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H). LC-MS(m/z) 422.1 (MH⁺); t_(R)=2.03 (Method C).

Example 128:5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 5-methyl-1,2,4-oxadiazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26 (dd, J=2.0, 7.2 Hz, 1H), 8.18(dd, J=2.0, 4.2 Hz, 1H), 7.24 (s, 1H), 7.03 (dd, J=4.4, 7.2 Hz, 1H),5.17 (br. s, 1H), 4.65-4.60 (m, 3H), 4.50 (q, J=7.2 Hz, 2H), 2.65 (s,3H), 2.64 (s, 3H), 2.23-2.16 (m, 1H), 1.93-1.90 (m, 1H), 1.64 (d, J=6.4Hz, 3H), 1.44 (t, J=6.8 Hz, 3H), 0.92 (t, J=7.6 Hz, 3H). LC-MS (m/z)422.1 (MH⁺); t_(R)=2.05 (Method C).

Example 129:5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methyloxazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 2-methyloxazole-4-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): =8.27 (dd, J=2.0, 7.2 Hz, 1H), 8.18 (dd,J=2.0, 5.2 Hz, 1H), 7.54 (s, 1H), 7.18 (s, 1H), 7.03 (dd, J=4.8, 7.2 Hz,1H), 5.11-4.91 (m, 1H), 4.61-4.55 (m, 1H), 4.48 (q, J=7.2 Hz, 2H), 4.40(d, J=4.8 Hz, 2H), 2.65 (s, 3H), 2.49 (s, 3H), 2.21-2.14 (m, 1H),1.92-1.85 (m, 1H), 1.63 (s, 3H), 1.40 (t, J=7.2 Hz, 3H), 0.89 (t, J=7.2Hz, 3H). LC-MS (m/z) 421.1 (MH⁺); t=1.9 (Method A).

Example 130:5-(2-ethoxy-3-pyridyl)-N-(1H-imidazol-4-ylmethyl)-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1H-imidazole-4-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): β=8.25 (dd, J=2.0, 7.2 Hz, 1H), 8.17(dd, J=2.0, 4.8 Hz, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.21 (s, 1H), 7.03 (s,1H), 7.02-7.00 (m, 1H), 5.57-5.08 (m, 1H), 4.63-4.60 (m, 1H), 4.50-4.51(m, 4H), 2.64 (s, 3H), 2.18-2.12 (m, 1H), 1.90-1.85 (m, 1H), 1.61 (d,J=6.4 Hz, 3H), 1.41 (t, J=7.2 Hz, 3H), 0.87 (t, J=7.2 Hz, 3H). LC-MS(m/z) 406.1 (MH⁺); t_(R)=1.35 (Method A).

Example 131:5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 5-methyl-1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): β=8.27 (dd, J=2.0, 7.2 Hz, 1H), 8.18(dd, J=2.0, 4.8 Hz, 1H), 7.20 (s, 1H), 7.04-7.01 (m, 1H), 6.08 (s, 1H),5.28 (brs, 1H), 4.61-4.58 (m, 1H), 4.51-4.46 (m, 4H), 2.65 (s, 3H), 2.35(s, 3H), 2.21-2.14 (m, 1H), 1.91-1.85 (m, 1H), 1.62 (d, J=6.8 Hz, 3H),1.43 (t, J=6.8 Hz, 3H), 0.89 (t, J=7.6 Hz, 3H). LC-MS (m/z) 420.1 (MH⁺);t_(R)=1.85 (Method A).

Example 132:5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methylimidazol-4-yl)methyl]-1-[1-methylpropy]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1-methyl-1H-imidazole-4-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): β=8.28 (dd, J=2.0, 7.6 Hz, 1H), 8.17(dd, J=2.0, 4.8 Hz, 1H), 7.45 (s, 1H), 7.20 (s, 1H), 7.04-7.01 (m, 1H),6.88 (s, 1H), 5.25 (brs, 1H), 4.61-4.58 (m, 1H), 4.48 (q, J=6.8 Hz, 2H),4.42 (d, J=4.8 Hz, 2H), 3.70 (s, 3H), 2.65 (s, 3H), 2.18-2.13 (m, 1H),1.89-1.85 (m, 1H), 1.60 (d, J=6.8 Hz, 3H), 1.42 (t, J=6.8 Hz, 3H), 0.88(t, J=7.2 Hz, 3H). LC-MS (m/z) 420.1 (MH⁺); t_(R)=1.38 (Method A).

Example 133:5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methyloxazol-5-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 2-methyloxazole-5-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): β=8.27 (dd, J=2.0, 7.6 Hz, 1H), 8.18(dd, J=2.0, 4.8 Hz, 1H), 7.25 (s, 1H), 7.03 (dd, J=4.8, 7.6 Hz, 1H),6.94 (s, 1H), 4.62 (brd, J=4.8 Hz, 1H), 4.55-4.46 (m, 5H), 2.65 (s, 3H),2.47 (s, 3H), 2.21-2.13 (m, 1H), 1.91-1.84 (m, 1H), 1.62 (d, J=6.8 Hz,3H), 1.41 (t, J=6.8 Hz, 3H), 0.87 (t, J=7.6 Hz, 3H). LC-MS (m/z) 421.1(MH⁺); t_(R)=1.81 (Method A).

Example134:3-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1-methyl-1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.27-8.25 (m, 1H), 8.19-8.17 (m, 1H),8.06 (s, 1H), 7.19 (s, 1H), 7.04-7.01 (m, 1H), 5.50-5.48 (m, 1H),4.71-4.66 (m, 1H), 4.56 (d, J=2.2 Hz, 2H), 4.39 (t, J=6.8 Hz, 2H), 3.96(s, 3H), 2.66 (s, 3H), 2.24-2.18 (m, 1H), 1.91-1.83 (m, 3H), 1.65 (d,J=3.2 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H). LC-MS(m/z) 435.1 (MH⁺); t_(R)=2.05 (Method C).

Example 135:3-methyl-1-[1-methylpropyl]-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 12.66 (s, 1H), 8.16-8.11 (m, 2H), 7.57(s, 1H), 7.10-7.06 (m, 2H), 6.71 (t, J=6.0 Hz, 1H), 6.15-6.14 (m, 1H),4.93-4.91 (m, 1H), 4.50 (d, J=5.6 Hz, 2H), 4.26 (t, J=6.8 Hz, 2H), 2.45(s, 3H), 2.00-1.92 (m, 1H), 1.76-1.67 (m, 3H), 1.47 (d, J=6.4 Hz, 3H),0.94 (t, J=7.2 Hz, 3H), 0.73 (t, J=7.2 Hz, 3H). LC-MS (m/z) 420.1 (MH⁺);t_(R)=2.1 (Method C).

Example 136:5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 and 1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.24-8.19 (m, 3H), 7.62 (d, J=2.0 Hz,1H), 7.23 (s, 1H), 7.04-7.01 (m, 1H), 6.37 (d, J=2.4 Hz, 1H), 5.45 (s,1H), 4.71-4.67 (m, 1H), 4.59 (d, J=4.8 Hz, 2H), 4.49 (q, J=6.8 Hz, 2H),2.25-2.18 (m, 1H), 1.94-1.90 (m, 1H), 1.66 (d, J=6.4 Hz, 3H), 1.44 (t,J=7.2 Hz, 3H), 0.9 (t, J=7.2 Hz, 3H). SFC; t_(R)=4.729 min, ee %=97.49%.LC-MS (m/z) 392 (MH⁺); t_(R)=2.23 (Method A).

Example 137:5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.24-8.18 (m, 3H), 7.61 (d, J=2.4 Hz,1H), 7.23 (s, 1H), 7.04-7.01 (m, 1H), 6.37 (d, J=2.4 Hz, 1H), 5.44 (s,1H), 4.71-4.67 (m, 1H), 4.59 (d, J=4.8 Hz, 2H), 4.49 (q, J=6.8 Hz, 2H),2.25-2.18 (m, 1H), 1.96-1.90 (m, 1H), 1.66 (d, J=6.8 Hz, 3H), 1.43 (t,J=7.2 Hz, 3H), 0.9 (t, J=7.2 Hz, 3H). SFC; t_(R)=4.453 min, ee %=94.84%.LC-MS (m/z) 392.1 (MH⁺); t_(R)=2.23 (Method A).

Example 138:5-(2-ethoxy-3-pyridyl)-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 and 5-methyl-1,3,4-oxadiazole-2-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.24-8.20 (m, 3H), 7.25 (s, 1H), 7.03(dd, J=4.8, 7.2 Hz, 1H), 5.37 (brs, 1H), 4.73-4.69 (m, 3H), 4.51 (q,J=7.2 Hz, 2H), 2.58 (s, 3H), 2.27-2.19 (m, 1H), 1.97-1.93 (m, 1H), 1.68(d, J=6.4 Hz, 3H), 1.44 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H).SFC-MS: t_(R)=4.24 min, ee %=98.70%. LC-MS (m/z) 408 (MH⁺); t_(R)=2.4(Method C).

Example 139:5-(2-ethoxy-3-pyridyl)-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 5-methyl-1,3,4-oxadiazole-2-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.25-8.20 (m, 3H), 7.25 (s, 1H), 7.03(dd, J=4.8, 7.2 Hz, 1H), 5.31 (brs, 1H), 4.73-4.68 (m, 3H), 4.51 (q,J=7.2 Hz, 2H), 2.59 (s, 3H), 2.27-2.20 (m, 1H), 1.97-1.94 (m, 1H), 1.68(d, J=6.4 Hz, 3H), 1.45 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H).SFC-MS: t_(R)=3.997 min, ee %=97.68%. LC-MS (m/z) 408.1 (MH⁺); t_(R)=2.4(Method C).

Example 140:5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 and 1-methyl-1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.25-8.19 (m, 3H), 8.07 (s, 1H), 7.23(s, 1H), 7.03 (dd, J=4.8, 7.2 Hz, 1H), 5.61 (brs, 1H), 4.79-4.74 (m,1H), 4.59 (d, J=4.8 Hz, 2H), 4.50 (q, J=7.2 Hz, 2H), 3.96 (s, 3H),2.27-2.22 (m, 1H), 1.98-1.93 (m, 1H), 1.68 (d, J=6.8 Hz, 3H), 1.46 (t,J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H). SFC-MS: t_(R)=4.97 min, ee%=98.60%. LC-MS (m/z) 407 (MH⁺); t_(R)=2.44 (Method C).

Example 141:5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1-methyl-1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.24-8.19 (m, 3H), 8.07 (s, 1H), 7.23(s, 1H), 7.03 (dd, J=4.8, 7.2 Hz, 1H), 5.60 (brs, 1H), 4.78-4.73 (m,1H), 4.59 (d, J=4.8 Hz, 2H), 4.50 (q, J=7.2 Hz, 2H), 3.96 (s, 3H),2.27-2.22 (m, 1H), 1.98-1.93 (m, 1H), 1.68 (d, J=6.8 Hz, 3H), 1.46 (t,J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H). SFC-MS: t_(R)=4.66 min, ee%=96.90%. LC-MS (m/z) 407.1 (MH⁺); t_(R)=2.44 (Method C).

Example 142:1-isopropyl-3-methyl-N-[(1-methylimidazol-4-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from1-isopropyl-3-methyl-5-(2-propoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-methyl-1H-imidazole-4-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.28-8.26 (m, 1H), 8.20-8.18 (m, 1H),7.46 (s, 1H), 7.18 (s, 1H), 7.05-7.02 (m, 1H), 6.91 (s, 1H), 5.43 (brs,1H), 4.94-4.90 (m, 1H), 4.45-4.44 (m, 2H), 4.38 (t, J=6.8 Hz, 2H), 3.70(s, 3H), 2.65 (s, 3H), 1.87-1.78 (m, 2H), 1.62 (d, J=6.8 Hz, 6H), 1.05(t, J=7.6 Hz, 3H). LC-MS (m/z) 420.1 (MH⁺); t_(R)=1.75 (Method C).

Example 143:1-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from1-isopropyl-3-methyl-5-(2-propoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.25-8.23 (m, 1H), 8.19-8.17 (m, 1H),7.61 (d, J=1.2 Hz, 1H), 7.18 (s, 1H), 7.05-7.01 (m, 1H), 6.36 (d, J=1.2Hz, 1H), 5.40 (brs, 1H), 4.96-4.90 (m, 1H), 4.58 (d, J=2.4 Hz, 2H), 4.38(t, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.86-1.82 (m, 2H), 1.64 (d, J=3.2 Hz,6H), 1.05 (t, J=7.6 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺); t_(R)=1.83 (MethodA).

Example 144:5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for example 29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-3-carbaldehydefollowed by deprotection with TFA.

¹H NMR (Chloroform-d, 400 MHz): δ 11.58 (brs, 1H), 8.25 (d, J=2.0 Hz,1H), 8.23-8.17 (m, 2H), 7.19 (s, 1H), 7.01 (dd, J=4.8, 7.2 Hz, 1H), 5.51(brs, 1H), 4.69-4.66 (m, 3H), 4.48 (q, J=7.2 Hz, 2H), 2.66 (s, 3H),2.22-2.16 (m, 1H), 1.93-1.89 (m, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.42 (t,J=6.8 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H). LC-MS (m/z) 407.1 (MH⁺);t_(R)=1.91 (Method C) [α]_(D) ²⁰ −3.40 (c=1.0, DCM).

Example 145:1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from1-isopropyl-3-methyl-5-(2-propoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): β=8.26-8.23 (m, 1H), 8.19-8.17 (m, 1H),8.06 (s, 1H), 7.18 (s, 1H), 7.04-7.01 (m, 1H), 5.52-5.51 (m, 1H),5.01-4.95 (m, 1H), 4.57 (d, J=4.8 Hz, 2H), 4.38 (t, J=6.8 Hz, 2H), 3.95(s, 3H), 2.65 (s, 3H), 1.90-1.81 (m, 2H), 1.66 (d, J=6.4 Hz, 6H), 1.05(t, J=7.6 Hz, 3H). LC-MS (m/z) 421.1 (MH⁺); t_(R)=2.1 (Method B).

Example 146:1-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)-N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29, from1-isopropyl-3-methyl-5-(2-propoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amineand1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-3-carbaldehydefollowed by deprotection with TFA.

¹H NMR (Chloroform-d, 400 MHz): δ 8.20-8.17 (m, 2H), 8.14 (s, 1H), 7.14(s, 1H), 7.03 (dd, J=4.2, 7.6 Hz, 1H), 5.59 (brs, 1H), 5.00-4.94 (m,1H), 4.64 (s, 2H), 4.36 (t, J=6.8 Hz, 2H), 2.65 (s, 3H), 1.85-1.76 (m,2H), 1.65 (d, J=6.8 Hz, 6H), 1.01 (t, J=7.2 Hz, 3H). LC-MS (m/z) 407.1(MH⁺); t_(R)=1.91 (Method C).

Example 147:1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-thiazol-2-yl-pyrazolo[4,3-b]pyridin-7-amine

To a solution of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(50 mg, 0.14 mmol) in DMF (2 mL) was added 2-(tributylstannyl)thiazole(103 mg, 0.28 mmol) and Pd(PPh₃)₄ (16 mg, 0.013 mmol). The mixture wasbubbled with N₂ and heated at 80° C. for 2 hours. The mixture was cooledto room temperature. ethyl acetate (20 mL) and water (10 mL) were added.The organic layer was washed with water (10 mL×2), brine (10 mL), driedover Na₂SO₄, filtered and concentrated. The crude was purified bypreparative TLC (SiO₂, ethyl acetate) to give1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(thiazol-2-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine(10 mg).

¹H NMR (Chloroform-d, 400 MHz): δ 7.88 (d, J=3.2 Hz, 1H), 7.58 (s, 1H),7.46 (s, 2H), 7.40 (d, J=3.2 Hz, 1H), 4.75-4.68 (m, 1H), 4.54 (brs, 1H),4.46 (d, J=4.8 Hz, 2H), 3.94 (s, 3H), 2.65 (s, 3H), 1.58 (d, J=6.8 Hz,6H). LC-MS (m/z) 368 (MH⁺); t_(R)=1.91 (Method C).

Example 148:1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(5-methylthiazol-2-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 147, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-methyl-2-(tributylstannyl)thiazole.

¹H NMR (600 MHz, DMSO-d₆) δ 7.62 (s, 1H), 7.56 (s, 1H), 7.43 (s, 1H),7.20 (s, 1H), 6.86 (t, J=5.6 Hz, 1H), 5.16 (m, 1H), 4.41 (d, J=5.5 Hz,2H), 3.77 (s, 3H), 2.47 (s, 3H), 2.45 (s, 3H), 1.44 (d, J=6.3 Hz, 6H).LC-MS (m/z) 382.3 (MH⁺); t_(R)=0.51 (Method D).

Example 149:1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(4-methylthiazol-2-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 147, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 4-methyl-2-(tributylstannyl)thiazole.

¹H NMR (500 MHz, Chloroform-d) δ 7.60 (s, 1H), 7.47 (s, 1H), 7.45 (s,1H), 6.96 (s, 1H), 4.73 (m, 1H), 4.53 (s, 1H), 4.49 (s, 2H), 3.96 (s,3H), 2.65 (s, 3H), 2.55 (s, 3H), 1.59 (d, J=6.4 Hz, 6H). LC-MS (m/z)382.4 (MH⁺); t_(R)=0.51 (Method D).

Example 150:3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-5-methyl-oxazolidin-2-one

A mixture of5-bromo-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine(20 mg, 0.06 mmol), 5-methyloxazolidin-2-one (7 mg, 0.07 mmol),Pd₂(dba)₃ (5 mg, 0.006 mmol), Xantphos (10 mg, 0.02 mmol), Cs₂CO₃ (25mg, 0.08 mmol) in dioxane (2 mL) was stirred at 85° C. for 12 hours. Themixture was concentrated to give a residue. The residue was purified bypreparative HPLC to give3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-5-methyl-oxazolidin-2-one(15 mg).

¹H NMR (Chloroform-d, 400 MHz): β=7.59 (s, 1H), 7.55 (s, 2H), 4.80 (brd,J=6.8 Hz, 1H), 4.74-4.64 (m, 1H), 4.63-4.56 (m, 1H), 4.47 (dd, J=8.4,10.4 Hz, 1H), 4.39 (d, J=5.0 Hz, 2H), 3.98-3.93 (m, 1H), 3.92 (s, 3H),2.51 (s, 3H), 1.58 (s, 3H), 1.55 (d, J=6.3 Hz, 6H). LC-MS (m/z) 384.1(MH⁺); t_(R)=1.9 (Method C).

Example 151:3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]oxazolidin-2-one

Prepared using the same procedure as described for example 150, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand oxazolidin-2-one.

¹H NMR (600 MHz, DMSO-d₆) δ 7.65 (s, 1H), 7.45 (s, 1H), 7.41 (s, 1H),6.78 (t, J=5.7 Hz, 1H), 5.09 (m, 1H), 4.41 (m, 2H), 4.28 (d, J=5.6 Hz,2H), 4.19 (m, 2H), 3.77 (s, 3H), 2.36 (s, 3H), 1.40 (d, J=6.3 Hz, 6H).LC-MS (m/z) 370.2 (MH⁺); t_(R)=1.51 (Method J).

Example 152:1-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]azetidin-2-one

Prepared using the same procedure as described for example 150, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand azetidin-2-one.

¹H NMR (600 MHz, DMSO-de) δ 7.64 (s, 1H), 7.45 (s, 1H), 6.94 (s, 1H),6.81 (t, J=5.6 Hz, 1H), 5.07 (m, 1H), 4.27 (d, J=5.5 Hz, 2H), 3.77 (s,3H), 3.66 (s, 2H), 3.04 (t, J=4.5 Hz, 2H), 2.35 (s, 3H), 1.40 (d, J=6.3Hz, 6H). LC-MS (m/z) 354.2 (MH⁺); t_(R)=1.46 (Method K).

Example 153:1-tert-butyl-3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]imidazolidin-2-one

Prepared using the same procedure as described for example 150, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-(tert-butyl)imidazolidin-2-one.

¹H NMR (500 MHz, Chloroform-d) 7.71 (s, 1H), 7.61 (s, 1H), 7.48 (s, 1H),6.52 (t, J=5.6 Hz, 1H), 5.10-4.94 (m, 1H), 4.25 (d, J=5.6 Hz, 2H),3.91-3.82 (m 2H), 3.77 (s, 3H), 3.44 (t, J=7.9 Hz, 2H), 2.34 (s, 3H),1.48-1.23 (m, 15H). LC-MS (m/z) 425.2 (MH⁺); t_(R)=1.64 (Method K).

Example 154:1-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]pyrrolidin-2-one

Prepared using the same procedure as described for example 150, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand pyrrolidin-2-one.

¹H NMR (600 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.67 (s, 1H), 7.47 (s, 1H),6.70 (t, J=5.7 Hz, 1H), 5.08 (m, 1H), 4.26 (d, J=5.6 Hz, 2H), 4.06-3.96(m, 2H), 3.77 (s, 3H), 2.56 (t, J=8.0 Hz, 2H), 2.36 (s, 3H), 2.06-1.94(m, 2H), 1.39 (d, J=6.3 Hz, 6H). LC-MS (m/z) 368.2 (MH⁺); t_(R)=1.39(Method K).

Example 155:3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-4-methyl-oxazolidin-2-one

Prepared using the same procedure as described for example 150, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 4-methyloxazolidin-2-one.

¹H NMR (Chloroform-d, 400 MHz): δ=7.55 (d, J=2.4 Hz, 2H), 7.45 (s, 1H),5.14-5.03 (m, 1H), 4.73-4.64 (m, 1H), 4.62-4.51 (m, 2H), 4.38 (dd,J=5.0, 9.6 Hz, 2H), 4.07 (dd, J=4.5, 8.3 Hz, 1H), 3.92 (s, 3H), 2.51 (s,3H), 1.56 (dd, J=1.7, 6.5 Hz, 6H), 1.52 (d, J=6.2 Hz, 3H). LC-MS (m/z)384.1 (MH⁺); t_(R)=2 (Method B).

Example 156:4-ethyl-3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]oxazolidin-2-one

Prepared using the same procedure as described for example 150, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 4-ethyloxazolidin-2-one.

¹H NMR (Chloroform-d, 400 MHz): δ 7.55 (d, J=2.0 Hz, 2H), 7.46 (s, 1H),5.1-4.98 (m, 1H), 4.70-4.66 (m, 1H), 4.57-4.55 (m, 1H), 4.51 (t, J=8.8Hz, 1H), 4.40-4.36 (m, 2H), 4.21-4.18 (m, 1H), 3.92 (s, 3H), 2.50 (s,3H), 2.02-1.79 (m, 2H), 1.55 (d, J=4.8 Hz 6H), 0.93 (t, J=7.6 Hz, 3H).LC-MS (m/z) 398.1 (MH⁺); t_(R)=1.99 (Method C).

Example 157:N-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]methyl]-5-methoxy-pyridin-3-amine

A mixture ofN-[(5-bromo-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl)methyl]-5-methoxy-pyridin-3-amine(69 mg, 0.18 mmol), (2-ethoxy-3-pyridyl)boronic acid (59 mg, 0.35 mmol),Pd(dppf)Cl₂ (26 mg, 0.03 mmol), Cs₂CO₃ (115 mg, 0.35 mmol) in dioxane (3mL) and water (1 mL) was degassed and purged with N₂ 3 times, and thenthe mixture was stirred at 100° C. for 2 hours under a N₂ atmosphere.Water (20 mL) was added and the mixture was extracted with ethyl acetate(30 mL×3). The combined organic layers were washed with brine (20 mL),dried over Na₂SO₄ and concentrated. The crude mixture was purified bypreparative HPLC to giveN-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]methyl]-5-methoxy-pyridin-3-amine(48.16 mg).

¹H NMR (Chloroform-d, 400 MHz): δ 8.27 (dd, J=2.0, 7.6 Hz, 1H), 8.18(dd, J=2.0, 4.8 Hz, 1H), 8.00 (s, 1H), 7.81-7.80 (m, 2H), 7.05-7.02 (m,1H), 6.49-6.48 (m, 1H), 4.90-4.87 (m, 1H), 4.74 (d, J=5.6 Hz, 2H), 4.40(q, J=7.2 Hz, 2H), 4.18-4.16 (m, 1H), 3.83 (s, 3H), 2.72 (s, 3H), 1.58(d, J=7.2 Hz, 6H), 1.27 (t, J=7.2 Hz, 3H). LC-MS (m/z) 433.1 (MH⁺);t_(R)=1.88 (Method A).

Example 158:N-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]methyl]-1-methyl-1,2,4-triazol-3-amine

Prepared using the same procedure as described for example 157, fromN-[(5-bromo-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl)methyl]-1-methyl-1,2,4-triazol-3-amineand (2-ethoxy-3-pyridyl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.24 (dd, J=2.0, 7.6 Hz, 1H), 8.18(dd, J=2.0, 5.2 Hz, 1H), 7.99 (s, 1H), 7.67 (s, 1H), 7.03 (dd, J=4.8,7.2 Hz, 1H), 5.01-4.98 (m, 1H), 4.91 (d, J=6.0 Hz, 2H), 4.56 (t, J=6.0Hz, 1H), 4.45 (q, J=7.2 Hz, 2H), 3.77 (s, 3H), 2.70 (s, 3H), 1.58 (d,J=6.4 Hz, 6H), 1.34 (t, J=7.2 Hz, 3H). LC-MS (m/z) 407.1 (MH⁺);t_(R)=2.17 (Method C).

Example 159:5-(2-ethoxy-3-pyridyl)-1-isopropyl-7-[2-(5-methoxy-3-pyridyl)ethyl]-3-methyl-pyrazolo[4,3-b]pyridine

A mixture of5-(2-ethoxypyridin-3-yl)-7-ethynyl-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine(0.05 g, 0.16 mmol), 3-iodo-5-methoxy-pyridine (37 mg, 0.16 mmol), Cul(3 mg, 0.016 mmol), Pd(dppf)Cl₂ (11 mg, 0.016 mmol) and Et₃N (79 mg,0.78 mmol) in dioxane (3 mL) was stirred at 100° C. under a N₂atmosphere for 4 hours. The mixture was worked up with 4 other batches(each with same procedure and same amount of starting material). Themixture was concentrated and extracted with ethyl acetate (20 mL×2),dried over Na₂SO₄, and concentrated to give residue. The mixture waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=10/1 to 1/1) to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-7-((5-methoxypyridin-3-yl)ethynyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine(0.025 g). A mixture of5-(2-ethoxypyridin-3-yl)-1-isopropyl-7-((5-methoxypyridin-3-yl)ethynyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine(0.02 g, 0.047 mmol), Pd/C (0.005 g, 0.047 mmol, 10%), H₂ (15 psi) inethyl acetate (2 mL) was stirred at room temperature for 0.25 hour. Themixture was filtered and the filtrate was concentrated to give residue.The residue was purified by preparative HPLC to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-7-(2-(5-methoxypyridin-3-yl)ethyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine(7 mg).

¹H NMR (Chloroform-d, 400 MHz): β=8.27-8.24 (m, 1H), 8.24-8.14 (m, 3H),7.79 (s, 1H), 7.05 (dd, J=4.8, 7.2 Hz, 1H), 6.96 (t, J=2.0 Hz, 1H),4.98-4.79 (m, 1H), 4.48 (q, J=7.2 Hz, 2H), 3.81 (s, 3H), 3.43-3.29 (m,2H), 3.18-3.01 (m, 2H), 2.70 (s, 3H), 1.59 (d, J=6.8 Hz, 6H), 1.41 (t,J=6.8 Hz, 3H). LC-MS (m/z) 432.1 (MH⁺); t_(R)=1.97 (Method A).

Example 160:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-7-[2-(1-methyl-1,2,4-triazol-3-yl)ethyl]pyrazolo[4,3-b]pyridine

Prepared using the same procedure as described for example 159, from5-(2-ethoxypyridin-3-yl)-7-ethynyl-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridineand added 3-bromo-1-methyl-1H-1,2,4-triazole.

¹H NMR (Chloroform-d, 400 MHz): δ 8.23 (dd, J=2.0, 7.6 Hz, 1H), 8.19(dd, J=1.6, 4.4 Hz, 1H), 7.99 (s, 1H), 7.81 (s, 1H), 7.04 (dd, J=4.2,7.6 Hz, 1H), 5.11-5.04 (m, 1H), 4.48 (q, J=7.2 Hz, 2H), 3.90 (s, 3H),3.55-3.51 (m, 2H), 3.23-3.18 (m, 2H), 2.70 (s, 3H), 1.61 (d, J=6.8 Hz,6H), 1.43 (t, J=6.8 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺); t_(R)=2.3 (MethodC).

Example 161:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amineand Example 162:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-1-[(4-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Cs₂CO₃ (16.6 mg, 0.051 mmol) and iodomethane (510 μl, 0.051 mmol, 100mM, THF) were added toN-((4H-1,2,4-triazol-3-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(20 mg, 0.051 mmol) in THF (1.3 mL). The reaction mixture was stirred ina sealed vial at 80° C. for 50 minutes. The reaction mixture wasconcentrated in vacuo. Water was added. The mixture was extracted withethyl acetate. The organic phase was washed with brine, dried overMgSO4, filtered and concentrated in vacuo. The residue was purified bySFC to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(2 mg) and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(1 mg)

Example 161

5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine:¹H NMR (600 MHz, Chloroform-d) δ 8.28 (dt, J=7.3, 1.4 Hz, 1H), 8.19 (dd,J=4.9, 1.9 Hz, 1H), 7.92 (s, 1H), 7.17 (s, 1H), 7.05 (dd, J=7.3, 4.9 Hz,1H), 5.72 (s, 1H), 4.98 (hept, J=6.6 Hz, 1H), 4.56 (d, J=4.1 Hz, 2H),4.49 (q, J=7.0 Hz, 2H), 3.95 (s, 3H), 2.66 (s, 3H), 1.66 (d, J=6.5 Hz,6H), 1.44 (t, J=7.0 Hz, 3H). LC-MS (m/z) 407.4 (MH⁺); t_(R)=0.51 (MethodD).

Example 162

5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine:¹H NMR (600 MHz, DMSO-d₆) δ 8.43 (s, 1H), 8.19 (dd, J=4.9, 1.9 Hz, 1H),8.12 (dd, J=7.3, 2.0 Hz, 1H), 7.32 (s, 1H), 7.09 (dd, J=7.4, 4.8 Hz,1H), 6.80 (t, J=5.2 Hz, 1H), 5.17 (hept, J=6.8 Hz, 1H), 4.67 (d, J=5.0Hz, 2H), 4.42 (q, J=7.0 Hz, 2H), 3.71 (s, 3H), 2.46 (s, 3H), 1.45 (d,J=6.3 Hz, 6H), 1.36 (t, J=7.0 Hz, 3H). LC-MS (m/z) 407.4 (MH⁺);t_(R)=0.49 (Method D).

Example 163:5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine

A suspension of5-(2-ethoxypyridin-3-yl)-3-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(80 mg, 0.22 mmol, prepared using the same procedure as described forexample 29, from5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine and1-methyl-1,2,4-triazole-3-carbaldehyde), 3-iodooxetane (81 mg, 0.44mmol) and t-BuOK (215 mg, 1.91 mmol) in DMF (2 mL) was heated to 120° C.for 34 hours. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was purified by preparative HPLCtwice to give5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-(oxetan-3-ylpyrazolo[4,3-b]pyridin-7-amine(8 mg).

¹H NMR (Chloroform-d, 400 MHz) δ 8.28 (dd, J=2.2, 7.4 Hz, 1H), 8.19 (dd,J=2.0, 4.8 Hz, 1H), 8.06 (s, 1H), 7.26 (s, 1H), 7.03 (dd, J=4.8, 7.4 Hz,1H), 5.97-5.93 (m, 1H), 5.34 (t, J=6.4 Hz, 2H), 5.19 (t, J=7.2 Hz, 2H),4.57 (d, J=5.2 Hz, 2H), 4.49 (q, J=6.8 Hz, 2H), 3.96 (s, 3H), 2.67 (s,3H), 1.44 (t, J=7.2 Hz, 3H). LC-MS (m/z) 421.1 (MH⁺); t_(R)=2.04 (MethodB).

Example 164:5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylsulfanyl]pyrazolo[4,3-b]pyridine

KO^(t)Bu (6.9 mg, 0.06 mmol) was added to a solution of 6-methylheptyl3-((5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thio)propanoate(21 mg, 0.04 mmol) in DMF (0.59 mL) at rt. The resulting mixture wasstirred at rt over 50 minutes after which4-(chloromethyl)-1-methyl-1H-pyrazole (13.4 mg, 0.06 mmol) was added inone portion. After stirring at rt over 6 hours the mixture was cooled toice bath temperature, quenched with a few drops of water and stirredwithout cooling bath for 5 minutes. Partitioned between ethyl acetate(40 mL) and water (2×15 mL). The org. layer was further washed withbrine (10 mL). The combined org. layers were dried (Na₂SO₄) andconcentrated. The crude material was purified by flash chromatographywith heptane:ethyl acetate 1:0 to 0:1 to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-7-(((1-methyl-1H-pyrazol-4-yl)methyl)thio)-1H-pyrazolo[4,3-b]pyridine(8 mg).

¹H NMR (DMSO-d₆ 600 MHz): δ 8.28-8.22 (m, 2H), 7.94 (s, 1H), 7.76 (s,1H), 7.47 (s, 1H), 7.16 (dd, J=7.3, 4.9 Hz, 1H), 5.33 (hept, J=6.5 Hz,1H), 4.44 (q, J=7.0 Hz, 2H), 4.39 (s, 2H), 3.79 (s, 3H), 2.54 (s, 3H),1.47 (d, J=6.5 Hz, 6H), 1.34 (t, J=7.0 Hz, 3H). LC-MS (m/z) 423.6 (MH⁺);t_(R)=0.76 (Method D).

Example 165:N-[[1-(difluoromethyl)pyrazol-4-yl]methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

To a solution ofN-((1-(difluoromethyl)-1H-pyrazol-4-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(15 mg, 0.027 mmol) in DCM (0.5 mL) was added trifluoro acetic acid (0.5mL). The mixture was stirred at room temperature for 1 hour. Water (3mL) was added and the mixture was poured into a saturated, aqueoussolution of NaHCO₃. The mixture was extracted with ethyl acetate (5mL×3). The combined organic layers were washed with brine (5 mL), driedover Na₂SO₄ and concentrated. The crude mixture was purified by flashchromatography with heptane:ethyl acetate=1:0 to 0:1 to giveN-((1-(difluoromethyl)-1H-pyrazol-4-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(11 mg, 0.025 mmol, 93% yield).

¹H NMR (600 MHz, Chloroform-d) δ 8.26 (dd, J=7.4, 2.0 Hz, 1H), 8.17 (dd,J=4.9, 2.0 Hz, 1H), 7.84 (d, J=2.7 Hz, 1H), 7.20 (s, 1H), 7.17 (t,J=60.7 Hz, 1H), 7.02 (dd, J=7.3, 4.9 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H),5.24 (s, 1H), 4.91 (hept, J=6.6 Hz, 1H), 4.57 (d, J=4.8 Hz, 2H), 4.47(q, J=7.0 Hz, 2H), 2.65 (s, 3H), 1.65 (d, J=6.5 Hz, 6H), 1.40 (t, J=7.0Hz, 3H). LC-MS (m/z) 442.5 (MH⁺); t_(R)=0.60 minutes (Method D).

Example 166:5-(2-ethoxypyridin-3-yl)-N-((5-(fluoromethyl)isoxazol-3-yl)methyl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 165, from5-(2-ethoxypyridin-3-yl)-N-((5-(fluoromethyl)isoxazol-3-yl)methyl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

¹H NMR (600 MHz, Chloroform-d) δ 8.27 (dd, J=7.4, 2.0 Hz, 1H), 8.18 (dd,J=4.9, 2.0 Hz, 1H), 7.22 (s, 1H), 7.02 (dd, J=7.4, 4.9 Hz, 1H), 6.47 (d,J=2.6 Hz, 1H), 5.43 (d, J=47.3 Hz, 2H), 5.22 (s, 1H), 4.89 (hept, J=6.6Hz, 1H), 4.65 (d, J=5.2 Hz, 2H), 4.47 (q, J=7.0 Hz, 2H), 2.64 (s, 3H),1.64 (d, J=6.5 Hz, 6H), 1.39 (t, J=7.0 Hz, 3H). LC-MS (m/z) 425.6 (MH⁺);t_(R)=0.57 minutes (Method D).

Example 167:5-(2-ethoxypyridin-3-yl)-N-((3-(fluoromethyl)isoxazol-5-yl)methyl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 165, from5-(2-ethoxypyridin-3-yl)-N-((3-(fluoromethyl)isoxazol-5-yl)methyl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

¹H NMR (600 MHz, Chloroform-d) δ 8.28 (dd, J=7.4, 2.0 Hz, 1H), 8.17 (dd,J=4.9, 2.0 Hz, 1H), 7.22 (s, 1H), 7.02 (dd, J=7.4, 4.9 Hz, 1H), 6.41 (s,1H), 5.44 (d, J=46.9 Hz, 2H), 4.90 (t, J=5.9 Hz, 1H), 4.84 (hept, J=6.6Hz, 1H), 4.73 (d, J=5.8 Hz, 2H), 4.45 (q, J=7.0 Hz, 2H), 2.65 (s, 3H),1.64 (d, J=6.5 Hz, 6H), 1.35 (t, J=7.0 Hz, 3H). LC-MS (m/z) 425.6 (MH⁺);t_(R)=0.55 minutes (Method D).

Example 168:1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-oxazol-2-yl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 147 from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand tributyl(oxazol-2-yl)stannane.

¹H NMR (Chloroform-d, 400 MHz): δ 7.83 (s, 1H), 7.59 (s, 1H), 7.46 (s,1H), 7.39 (s, 1H), 7.29 (s, 1H), 4.76-4.70 (m, 1H), 4.58 (brs, 1H), 4.44(d, J=4.2 Hz, 2H), 3.94 (s, 3H), 2.69 (s, 3H), 1.59 (d, J=6.4 Hz, 6H).LC-MS (m/z) 352 (MH⁺); t_(R)=1.75 minutes (Method C).

Example 169:1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(3-methyltriazol-4-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 147 from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole.

¹H NMR (Chloroform-d, 400 MHz): δ 7.93 (s, 1H), 7.57 (s, 1H), 7.45 (s,1H), 6.70 (s, 1H), 4.76-4.69 (m, 1H), 4.65 (brs, 1H), 4.48 (s, 3H), 4.39(d, J=4.4 Hz, 2H), 3.95 (s, 3H), 2.62 (s, 3H), 1.60 (d, J=6.4 Hz, 6H).LC-MS (m/z) 366 (MH⁺); t_(R)=1.69 minutes (Method C).

Example 170:1-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from[2-(trifluoromethyl)-3-pyridyl]methanamine,(2-methoxypyridin-3-yl)boronic acid and5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.67 (d, J=4.0 Hz 1H), 8.20 (dd,J=1.2, 7.2 Hz 1H), 8.15 (dd, J=2.0, 4.8 Hz 1H), 7.99 (d, J=7.6 Hz 1H),7.50 (dd, J=4.8, 8.0 Hz 1H), 7.01 (dd, J=5.2, 7.6 Hz 1H), 6.90 (s, 1H),5.07 (brs, 1H), 4.86-4.89 (m, 3H), 3.74 (s, 3H), 2.65 (s, 3H), 1.66 (d,J=6.8 Hz, 6H). LC-MS (m/z) 457 (MH⁺); t_(R)=1.89 minutes (Method A).

Example 171:3-[1-isopropyl-7-[(2-methoxy-3-pyridyl)methylamino]-3-methyl-pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one

Prepared using the same procedure as described for example 1 from5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-methoxypyridin-3-yl)methanamine and(2-oxo-1,2-dihydropyridin-3-yl)boronic acid.

¹H NMR (DMSO-de, 400 MHz): δ 11.73 (brs, 1H), 8.27 (dd, J=2.0, 7.2 Hz,1H), 8.01 (d, J=3.6 Hz, 1H), 7.57 (d, J=6.4 Hz, 1H), 7.45-7.35 (m, 1H),6.88 (dd, J=4.2, 7.2 Hz, 1H), 6.75-6.67 (m, 1H), 6.35-6.25 (m, 1H),5.20-5.14 (m, 1H), 4.45-4.40 (m, 2H), 3.91 (s, 3H), 2.43 (s, 3H), 1.43(d, J=6.4 Hz, 6H). LC-MS (m/z) 405 (MH⁺); t_(R)=1.95 minutes (Method C).

Example 172:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methoxy-4-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(3-methoxy-4-pyridyl)methanamine and (2-ethoxy-3-pyridyl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.32 (s, 1H), 8.26 (d, J=4.8 Hz, 1H),8.22 (d, J=7.2 Hz, 1H), 8.14 (d, J=4.2 Hz, 1H), 7.30-7.25 (m, 1H), 7.08(s, 1H), 7.01 (dd, J=4.8, 7.2 Hz, 1H), 5.02 (brs, 1H), 4.91-4.88 (m,1H), 4.58 (d, J=5.6 Hz, 2H), 4.35 (q, J=7.2 Hz, 2H), 4.01 (s, 3H), 2.65(s, 3H), 1.66 (d, J=7.2 Hz, 6H), 1.26 (t, J=7.2 Hz, 3H). LC-MS (m/z)433.1 (MH⁺); t_(R)=1.47 minutes (Method A).

Example 173:1-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29 from1-isopropyl-5-(2-methoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-methylthiazole-5-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.20-8.18 (m, 2H), 7.64 (s, 1H), 7.12(s, 1H), 7.07-7.04 (m, 1H), 4.88-4.77 (m, 2H), 4.77-4.68 (m, 2H), 4.00(s, 3H), 2.72 (s, 3H), 2.65 (s, 3H), 1.62 (d, J=6.8 Hz, 6H). LC-MS (m/z)409 (MH⁺); t=1.66 minutes (Method A).

Example 174:5-(2-cyclopropoxypyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-methoxypyridin-3-yl)methanamine and2-cyclopropoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

¹H NMR (Chloroform-d, 600 MHz) δ 8.23 (dd, J=4.9, 2.0 Hz, 1H), 8.21 (dd,J=7.4, 2.0 Hz, 1H), 8.14 (dd, J=5.0, 1.9 Hz, 1H), 7.59 (dd, J=7.2, 1.8Hz, 1H), 7.05 (dd, J=7.4, 4.9 Hz, 1H), 6.97 (s, 1H), 6.90 (dd, J=7.2,5.0 Hz, 1H), 5.11 (t, J=5.8 Hz, 1H), 4.86 (hept, J=6.5 Hz, 1H), 4.48 (d,J=5.8 Hz, 2H), 4.39-4.34 (m, 1H), 4.04 (s, 3H), 2.63 (s, 3H), 1.63 (d,J=6.6 Hz, 6H), 0.79-0.76 (m, 2H), 0.63-0.60 (m, 2H). LC-MS (m/z) 445.5(MH⁺); t_(R)=0.6 minutes (Method D).

Example 175:1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-methoxypyridin-3-yl)methanamine and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

¹H NMR (Chloroform-d, 600 MHz) δ 8.15 (dd, J=5.1, 1.9 Hz, 1H), 7.60 (dd,J=7.2, 1.8 Hz, 1H), 7.48 (d, J=1.9 Hz, 1H), 6.91 (dd, J=7.2, 5.0 Hz,1H), 6.64 (s, 1H), 6.44 (d, J=2.0 Hz, 1H), 5.22 (t, J=5.9 Hz, 1H), 4.84(hept, J=6.6 Hz, 1H), 4.49 (d, J=5.8 Hz, 2H), 4.22 (s, 3H), 4.04 (s,3H), 2.60 (s, 3H), 1.63 (d, J=6.5 Hz, 6H). LC-MS (m/z) 392.5 (MH⁺);t_(R)=0.49 minutes (Method D).

Example 176:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxypyrimidin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(5-methoxypyrimidin-2-yl)methanamine and (2-ethoxy-3-pyridyl)boronicacid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.48 (s, 2H), 8.27 (d, J=7.6 Hz, 1H),8.20 (d, J=4.0 Hz, 1H), 7.16 (s, 1H), 7.04 (dd, J=4.8, 6.8 Hz, 1H),5.15-5.08 (m, 1H), 4.68 (d, J=4.4 Hz, 2H), 4.50 (q, J=7.2 Hz, 2H), 3.98(s, 3H), 2.70 (s, 3H), 1.71 (d, J=6.4 Hz, 6H), 1.45 (t, J=6.8 Hz, 3H).LC-MS (m/z) 434.1 (MH⁺); t_(R)=2.15 minutes (Method C).

Example 177:3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one

Prepared using the same procedure as described for example 1 from5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(1-methyl-1H-pyrazol-4-yl)methanamine and(2-oxo-1,2-dihydropyridin-3-yl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.22 (d, J=6.8 Hz, 1H), 7.90-7.75 (m,1H), 7.59 (s, 1H), 7.57 (s, 1H), 7.26-7.20 (m, 1H), 6.65-6.63 (m, 1H),5.47 (brs, 1H), 4.96-4.90 (m, 1H), 4.52 (d, J=4.4 Hz, 2H), 3.92 (s, 3H),2.60 (s, 3H), 1.59 (d, J=6.4 Hz, 6H). LC-MS (m/z) 378 (MH⁺); t_(R)=1.71minutes (Method C).

Example 178:N-[[2-(difluoromethyl)-3-pyridyl]methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-(difluoromethyl)pyridin-3-yl)methanamine and(2-ethoxy-3-pyridyl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.58 (d, J=4.4 Hz, 1H), 8.24 (dd,J=7.6, 2.0 Hz, 1H), 8.14 (dd, J=4.8, 2.0 Hz, 1H), 7.92 (d, J=7.6 Hz,1H), 7.42 (dd, J=8.0, 5.2 Hz, 1H), 7.13 (s, 1H), 7.00 (dd, J=7.2, 4.8Hz, 1H), 6.80 (t, J=54.8 Hz, 1H), 4.97-4.82 (m, 4H), 4.33 (q, J=6.8 Hz,2H), 2.66 (s, 3H), 1.64 (d, J=6.4 Hz, 6H), 1.21 (t, J=6.8 Hz, 3H) LC-MS(m/z) 453.1 (MH⁺); t_(R)=1.98 minutes (Method A).

Example 179:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxypyrimidin-4-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(6-methoxypyrimidin-4-yl)methanamine and (2-ethoxy-3-pyridyl)boronicacid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.82 (s, 1H), 8.25 (dd, J=5.2, 7.2 Hz,1H), 8.17 (dd, J=2.0, 5.2 Hz, 1H), 7.08 (s, 1H), 7.02 (dd, J=4.8, 7.2Hz, 1H), 6.78 (s, 1H), 6.01 (brs, 1H), 5.06-5.00 (m, 1H), 4.54 (d, J=4.4Hz, 2H), 4.43 (q, J=6.8 Hz, 2H), 4.01 (s, 3H), 2.66 (s, 3H), 1.69 (d,J=6.8 Hz, 6H), 1.36 (t, J=6.8 Hz, 3H) LC-MS (m/z) 434.1 (MH⁺); t_(R)=1.9minutes (Method A).

Example 180:5-(2-(ethoxy-1,1-d₂)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5-bromo-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand2-(ethoxy-1,1-d₂)-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2yl)pyridine.

¹H NMR (Chloroform-d, 600 MHz) δ 8.24 (dd, J=7.3, 2.0 Hz, 1H), 8.12-8.15(m, 2H), 7.59 (ddt, J=7.2, 1.8, 0.8 Hz, 1H), 7.14 (s, 1H), 6.99 (dd,J=7.4, 4.9 Hz, 1H), 6.89 (dd, J=7.2, 5.0 Hz, 1H), 5.10 (t, J=5.8 Hz,1H), 4.87 (hept, J=6.6 Hz, 1H), 4.50 (d, J=5.7 Hz, 2H), 4.03 (s, 3H),2.64 (s, 3H), 1.63 (d, J=6.5 Hz, 6H), 1.29 (s, 3H). LC-MS (m/z) 435.6(MH⁺); t_(R)=0.61 minutes (Method D).

Example 181:5-(2-(ethoxy-d₅)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5-bromo-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-(ethoxy-d₅)-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2yl)pyridine.

¹H NMR (Chloroform-d, 600 MHz) δ 8.24 (ddd, J=7.4, 2.0, 0.7 Hz, 1H),8.12-8.15 (m, 2H), 7.61-7.56 (m, 1H), 7.14 (s, 1H), 7.02-6.96 (m, 1H),6.89 (dd, J=7.2, 5.0 Hz, 1H), 5.10 (t, J=5.8 Hz, 1H), 4.87 (hept, J=6.6Hz, 1H), 4.50 (d, J=5.7 Hz, 2H), 4.03 (s, 3H), 2.64 (s, 3H), 1.63 (d,J=6.5 Hz, 6H). LC-MS (m/z) 438.6 (MH⁺); t_(R)=0.6 minutes (Method D).

Example 182:5-(2-(ethoxy-2,2,2-d)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5-bromo-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand2-(ethoxy-2,2,2-d₃)-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2yl)pyridine.

¹H NMR (Chloroform-d, 600 MHz) δ 8.24 (dd, J=7.4, 2.0 Hz, 1H), 8.12-8.16(m, 2H), 7.59 (ddd, J=7.3, 1.9, 0.9 Hz, 1H), 7.14 (s, 1H), 6.99 (dd,J=7.4, 4.9 Hz, 1H), 6.89 (dd, J=7.2, 5.0 Hz, 1H), 5.10 (t, J=5.8 Hz,1H), 4.87 (hept, J=6.6 Hz, 1H), 4.50 (d, J=5.7 Hz, 2H), 4.38 (s, 2H),4.03 (s, 3H), 2.64 (s, 3H), 1.63 (d, J=6.5 Hz, 6H). LC-MS (m/z) 436.6(MH⁺); t_(R)=0.6 minutes (Method D).

Example 183:1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-5-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example from5-bromo-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand (2-(trifluoromethyl)pyridin-3-yl)boronic acid.

¹H NMR (Chloroform-d, 600 MHz) δ 8.73 (dd, J=4.7, 1.6 Hz, 1H), 8.13 (dd,J=5.1, 1.9 Hz, 1H), 7.94 (dd, J=7.9, 1.6 Hz, 1H), 7.57-7.52 (m, 2H),6.89 (dd, J=7.2, 5.1 Hz, 1H), 6.49 (s, 1H), 5.29 (t, J=5.8 Hz, 1H), 4.87(hept, J=6.6 Hz, 1H), 4.45 (d, J=5.8 Hz, 2H), 4.01 (s, 3H), 2.61 (s,3H), 1.66 (d, J=6.5 Hz, 6H). LC-MS (m/z) 457.5 (MH⁺); t_(R)=0.56 minutes(Method D).

Example 184:3-(difluoromethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

A solution of7-chloro-3-(difluoromethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine(3.0 mg, 6.5 μmol), (1-methyl-1H-pyrazol-4-yl)methanamine (29.0 mg, 0.26mmol) in NMP (0.22 ml) in a sealed vial was inserted in an oil bath at155° C. and stirred for 16 hours The mixture was partitioned betweenethyl acetate (20 ml) and water (2×15 ml). The organic layer was washedwith brine (10 ml), dried (Na₂SO₄) and concentrated. Flashchromatography on silica gel (elution gradient from heptane to ethylacetate) delivered3-(difluoromethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 600 MHz) δ 8.33 (dd, J=7.4, 2.0 Hz, 1H), 8.18 (dd,J=4.9, 2.0 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 1H), 7.35 (s, 1H), 7.16 (t,J=54.1 Hz, 1H), 7.03 (dd, J=7.4, 4.9 Hz, 1H), 4.82 (hept, J=6.5 Hz, 1H),4.57 (t, J=5.0 Hz, 1H), 4.47 (q, J=7.0 Hz, 2H), 4.40 (d, J=4.8 Hz, 2H),3.93 (s, 3H), 1.64 (d, J=6.5 Hz, 6H), 1.39 (t, J=7.0 Hz, 3H). LC-MS(m/z) 442.6 (MH⁺); t_(R)=0.55 minutes (Method D).

Example 185:1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(1H-1,2,4-triazol-1-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

A mixture of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(50 mg, 0.14 mmol), 1H-1,2,4-triazole (19 mg, 0.28 mmol), Cs₂CO₃ (135mg, 0.41 mmol) N₁,N₂-dimethylethane-1,2-diamine (2 mg, 0.028 mmol),iodocopper;tetrabutylammonium;diiodide (30 mg, 0.027 mmol) indimethylacetamide (2 mL) was stirred at 110° C. for 16 hours in a glovebox. After a filtration, the filtrate was concentrated and purified bypreparative HPLC to give1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(1H-1,2,4-triazol-1-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz): δ 9.24 (s, 1H), 8.08 (s, 1H), 7.58 (s,1H), 7.47 (s, 1H), 7.13 (s, 1H), 4.76-4.73 (m, 1H), 4.73-4.64 (m, 1H),4.45 (d, J=4.8 Hz, 2H), 3.95 (s, 3H), 2.59 (s, 3H), 1.59 (d, J=6.4 Hz,6H). LC-MS: t_(R)=1.88 min (Method B), m/z=352.1 [M+H]⁺.

Example 186:3-[1-isopropyl-3-methyl-7-[(1-methyl-1,2,4-triazol-3-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one

Prepared using the same procedure as described for example 29 from3-(7-amino-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2(1H)-oneand 1-methyl-1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.24-8.22 (m, 1H), 8.05 (s, 1H),8.02-7.98 (m, 1H), 7.21 (s, 1H), 6.79-6.74 (m, 1H), 6.00-5.94 (m, 1H),5.03-4.97 (m, 1H), 4.70 (d, J=4.4 Hz, 2H), 3.95 (s, 3H), 2.62 (s, 3H),1.65 (d, J=6.8 Hz, 6H). LC-MS (m/z) 379.1 (MH⁺); t_(R)=1.56 minutes(Method B).

Example 187:3-[1-isopropyl-3-methyl-7-(1H-pyrazol-3-ylmethylamino)pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one

Prepared using the same procedure as described for example 29 from3-(7-amino-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2(1H)-oneand 1H-pyrazole-3-carbaldehyde.

¹H NMR (DMSO-de, 400 MHz): δ 12.63 (brs, 1H), 11.73 (brs, 1H), 8.30-8.28(m, 1H), 7.82-7.47 (m, 3H), 6.62-6.51 (m, 1H), 6.32-6.21 (m, 2H),5.16-5.13 (m, 1H), 4.57-4.39 (m, 2H), 2.46 (s, 3H), 1.43 (d, J=6.4 Hz,6H). LC-MS (m/z) 364 (MH⁺); t_(R)=1.79 minutes (Method C).

Example 188:5-[2-(difluoromethoxy)-3-pyridyl]-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-methoxypyridin-3-yl)methanamine and(2-(difluoromethoxy)pyridin-3-yl)boronic acid. ¹H NMR (Chloroform-d, 600MHz) δ 8.38 (dd, J=7.5, 2.0 Hz, 1H), 8.19 (dd, J=4.8, 2.0 Hz, 1H), 8.12(dd, J=5.1, 1.9 Hz, 1H), 7.64 (dd, J=7.2, 1.7 Hz, 1H), 7.60 (t, J=73.1Hz, 1H), 7.24 (dd, J=7.5, 4.8 Hz, 1H), 7.05 (s, 1H), 6.90 (dd, J=7.2,5.0 Hz, 1H), 5.27 (t, J=6.0 Hz, 1H), 4.87 (hept, J=6.5 Hz, 1H), 4.51 (d,J=5.9 Hz, 2H), 4.03 (s, 3H), 2.62 (s, 3H), 1.64 (d, J=6.6 Hz, 6H). LC-MS(m/z) 455.6 (MH⁺); t_(R)=0.57 minutes (Method D).

Example 189:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxypyrimidin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(4-methoxypyrimidin-2-yl)methanamine and (2-ethoxy-3-pyridyl)boronicacid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.47 (d, J=5.6 Hz, 1H), 8.26 (dd,J=2.0, 7.6 Hz, 1H), 8.19 (dd, J=2.0, 4.8 Hz, 1H), 7.17 (s, 1H), 7.03(dd, J=4.8, 7.2 Hz, 1H), 6.71 (d, J=6.0 Hz, 1H), 6.35 (brs, 1H),5.16-5.10 (m, 1H), 4.62 (d, J=4.4 Hz, 2H), 4.50 (q, J=6.8 Hz, 2H), 4.04(s, 3H), 2.67 (s, 3H), 1.69 (d, J=6.4 Hz, 6H), 1.46 (t, J=6.8 Hz, 3H)LC-MS (m/z) 434.2 (MH⁺); t_(R)=1.75 minutes (Method A).

Example 190:5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxypyrimidin-5-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 165 from5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-(bromomethyl)-4-methoxypyrimidine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.77 (s, 1H), 8.49 (s, 1H), 8.24 (dd,J=2.0, 7.2 Hz, 1H), 8.17 (dd, J=2.0, 4.8 Hz, 1H), 7.16 (s, 1H), 7.02(dd, J=4.8, 7.2 Hz, 1H), 4.97-4.94 (m, 1H), 4.88-4.84 (m, 1H), 4.52 (d,J=5.6 Hz, 2H), 4.44 (q, J=7.2 Hz, 2H), 4.09 (s, 3H), 2.65 (s, 3H), 1.64(d, J=6.8 Hz, 6H), 1.34 (t, J=6.8 Hz, 3H). LC-MS (m/z) 434.1 (MH⁺);t_(R)=1.57 minutes (Method A).

Example 191:5-(2-ethoxy-3-pyridyl)-N-[(2-ethoxy-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-ethoxypyridin-3-yl)methanamine and (2-ethoxy-3-pyridyl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26-8.24 (m, 1H), 8.17-8.16 (m, 1H),8.12-8.11 (m, 1H), 7.60-7.59 (m, 1H), 7.17 (s, 1H), 7.03-7.00 (m, 1H),6.88-6.87 (m, 1H), 5.08 (brs, 1H), 4.89-4.86 (m, 1H), 4.53-4.45 (m, 4H),4.41 (q, J=6.8 Hz, 2H), 2.65 (s, 3H), 1.64 (d, J=6.4 Hz, 6H), 1.43 (t,J=7.2 Hz, 3H), 1.32 (t, J=7.2 Hz, 3H). LC-MS (m/z) 447.2 (MH⁺);t_(R)=1.9 minutes (Method A).

Example 192:5-[2-(dimethylamino)-3-pyridyl]-1-isopropyl-N-[(4-methoxyphenyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

To a solution of NaH (183 mg, 4.59 mmol, 60% w/w) in THF (4 mL) wasadded5-(2-fluoropyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(310 mg, 0.77 mmol) at 0° C. Dimethylamine hydrochloride (156 mg, 1.91mmol) was added and the resulting mixture was stirred at 70° C. for 16hours. Water (3 mL) was added and the mixture was poured into asaturated, aqueous solution of NaHCO₃. The mixture was extracted withethyl acetate (20 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄ and concentrated. The crude mixture waspurified by flash chromatography with heptane:ethyl acetate=1:0 to 0:1to give5-(2-(dimethylamino)pyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

¹H NMR (Chloroform-d, 600 MHz) δ 8.19 (dd, J=4.8, 1.9 Hz, 1H), 7.82 (dd,J=7.4, 1.9 Hz, 1H), 7.32 (d, J=8.6 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 6.82(dd, J=7.4, 4.8 Hz, 1H), 6.79 (s, 1H), 4.87-4.83 (m, 1H), 4.83-4.79 (m,1H), 4.42 (d, J=5.1 Hz, 2H), 3.83 (s, 3H), 2.64 (s, 3H), 2.61 (s, 6H),1.64 (d, J=6.6 Hz, 6H). LC-MS (m/z) 431.2 (MH⁺); t_(R)=0.42 minutes(Method D).

Example 193:3-[1-isopropyl-3-methyl-7-[[2-(trifluoromethyl)-3-pyridyl]methylamino]pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one

Prepared using the same procedure as described for example 1 from5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-(trifluoromethyl)pyridin-3-yl)methanamine and(2-oxo-1,2-dihydropyridin-3-yl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.64 (d, J=4.4 Hz, 1H), 8.08 (d, J=8.0Hz, 2H), 7.69 (m, 1H), 7.50-7.47 (m, 1H), 7.07 (m, 1H), 6.59-6.56 (m,1H), 6.06 (brs, 1H), 5.08 (m, 1H), 4.91 (s, 2H), 2.58 (s, 3H), 1.63 (d,J=6.4 Hz, 6H). LC-MS (m/z) 443 (MH⁺); t_(R)=1.87 minutes (Method C).

Example 194:1-isopropyl-3-methyl-5-(3-methylisoxazol-4-yl)-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole.

¹H NMR (Chloroform-d, 400 MHz): δ=8.67 (s, 1H), 7.56 (s, 1H), 7.43 (s,1H), 6.54 (s, 1H), 4.79-4.66 (m, 1H), 4.60 (brs, 1H), 4.38 (d, J=4.8 Hz,2H), 3.94 (s, 3H), 2.61 (s, 6H), 1.59 (d, J=6.4 Hz, 6H). LC-MS (m/z)366.1 (MH⁺); t_(R)=1.61 minutes (Method C).

Example 195:1-isopropyl-3-methyl-5-(1-methyl-H-1,2,4-triazol-5-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

A mixture of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(0.15 g, 0.41 mmol), 1-methyl-1H-1,2,4-triazole (103 mg, 1.24 mmol),Pd(OAc)₂ (5 mg, 0.021 mmol), Ru-Phos(2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl) (19 mg, 0.041mmol), K₂CO (171 mg, 1.24 mmol) and 2,2-dimethylpropanoic acid (21 mg,0.21 mmol) in xylene (15 mL) was stirred at 140° C. for 12 hours underN₂. The mixture was concentrated under vacuum. The residue was purifiedby preparative TLC (SiO₂, ethyl acetate/MeOH=10:1) and preparative HPLCto afford1-isopropyl-3-methyl-5-(1-methyl-1H-1,2,4-triazol-5-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz): δ 7.92 (s, 1H), 7.57 (s, 1H), 7.46 (s,1H), 7.42 (s, 1H), 4.76-4.70 (m, 1H), 4.59-4.56 (m, 1H), 4.47 (s, 3H),4.44 (d, J=4.4 Hz, 2H), 3.93 (s, 3H), 2.62 (s, 3H), 1.59 (d, J=6.4 Hz,6H). LC-MS (m/z) 366.1 (MH⁺); t_(R)=1.72 minutes (Method C).

Example 196:1-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29 from1-isopropyl-3-methyl-5-(2-propoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-trityl-1H-pyrazole-4-carbaldehyde.

¹H NMR (DMSO-de, 400 MHz): δ 8.27 (dd, J=7.2, 2.0 Hz, 1H), 8.18 (dd,J=4.8, 2.0 Hz, 1H), 7.70 (s, 2H), 7.24 (s, 1H), 7.03 (dd, J=7.6, 5.2 Hz,1H), 4.82-4.72 (m, 1H), 4.52 (brs, 1H), 4.45 (d, J=4.8 Hz, 2H), 4.37 (t,J=6.4 Hz, 2H), 2.65 (s, 3H), 1.86-1.77 (m, 2H), 1.6 (d, J=6.4 Hz, 6H),1.04 (t, J=7.6 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺); t_(R)=1.66 minutes(Method A).

Example 197:5-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 1 from5,7-dibromo-3-methyl-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridine,(2-methoxy-3-pyridyl)methanamine and (2-ethoxy-3-pyridyl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.27 (dd, J=2.0, 7.6 Hz, 1H),8.19-8.16 (m, 1H), 8.15-8.12 (m, 1H), 7.59 (d, J=6.4 Hz 1H), 7.23 (s,1H), 7.04-7.01 (m, 1H), 6.91-6.88 (m, 1H), 6.15 (brs, 1H), 5.90-5.86 (m,1H), 5.26-5.22 (m, 2H), 5.18-5.15 (m, 2H), 4.53 (d, J=5.6 Hz, 2H), 4.42(q, J=6.8 Hz, 2H) 4.03 (s, 3H), 2.64 (s, 3H), 1.32 (t, J=6.8 Hz, 3H).LC-MS (m/z) 447 (MH⁺); t_(R)=1.89 minutes (Method C).

Example 198:5-(2-(ethyl(methyl)amino)pyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 192 from5-(2-fluoropyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand methylethanamine.

¹H NMR (Chloroform-d, 600 MHz) δ 8.20 (dd, J=4.8, 1.9 Hz, 1H), 7.80 (dd,J=7.4, 1.9 Hz, 1H), 7.32 (d, J=8.7 Hz, 2H), 6.93 (d, J=8.6 Hz, 2H),6.84-6.80 (m, 2H), 4.79 (hept, J=6.6 Hz, 1H), 4.72 (t, J=5.2 Hz, 1H),4.40 (d, J=5.1 Hz, 2H), 3.83 (s, 3H), 3.08 (q, J=7.0 Hz, 2H), 2.65 (s,3H), 2.64 (s, 3H), 1.62 (d, J=6.5 Hz, 6H), 0.93 (t, J=7.0 Hz, 3H). LC-MS(m/z) 445.6 (MH⁺); t_(R)=0.53 minutes (Method D).

Example 199:5-(2-ethoxypyridin-3-yl)-3-(fluoromethyl)-1-isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

A solution of7-chloro-5-(2-ethoxypyridin-3-yl)-3-(fluoromethyl)-1-isopropyl-H-pyrazolo[4,3-b]pyridine(2.0 mg, 5.7 μmol), (1-methyl-1H-pyrazol-4-yl)methanamine (30.0 mg, 0.27mmol) in NMP (0.2 ml) in a sealed vial was inserted in an oil bath at155° C. After 20 hours (1-methyl-1H-pyrazol-4-yl)methanamine (30.0 mg,0.27 mmol) was added and the solution was heated at 155° C. for 15hours. The mixture was partitioned between ethyl acetate (25 ml) andwater (3×20 ml). The organic layer was washed with brine (25 ml), dried(Na₂SO₄) and concentrated. The residue was purified by flashchromatography on silica gel (heptane/ethyl acetate) to give5-(2-ethoxypyridin-3-yl)-3-(fluoromethyl)-1-isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (DMSO-de, 600 MHz) δ 8.21-8.15 (m, 2H), 7.61 (s, 1H), 7.42 (s,1H), 7.14 (s, 1H), 7.10 (dd, J=7.4, 4.9 Hz, 1H), 6.84 (t, J=5.6 Hz, 1H),5.67 (d, J=49.2 Hz, 2H), 5.28 (hept, J=6.4 Hz, 1H), 4.41-4.33 (m, 4H),3.77 (s, 3H), 1.51 (d, J=6.5 Hz, 6H), 1.24 (t, J=6.9 Hz, 3H). LC-MS(m/z) 424.6 (MH⁺); t_(R)=0.5 minutes (Method D).

Example 200:1-isopropyl-3-methyl-N-((1-methyl-H-pyrazol-4-yl)methyl)-5-(4-methyloxazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

A mixture of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1-pyrazolo[4,3-b]pyridin-7-amine(0.15 g, 0.41 mmol), 4-methyloxazole (103 mg, 1.2 mmol), Pd(OAc)₂ (5 mg,0.021 mmol), Ru-Phos (19 mg, 0.041 mmol), K₂CO₃ (171 mg, 1.2 mmol) and2,2-dimethylpropanoic acid (17 mg, 0.17 mmol) in toluene (15 mL) wasstirred at 110° C. for 12 hours. The mixture was concentrated undervacuum. The residue was purified by preparative TLC (SiO₂, petroleumether/ethyl acetate=0:1) and preparative HPLC to afford1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(4-methyloxazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz): δ 7.85 (s, 1H), 7.58 (s, 1H), 7.45 (s,1H), 6.84 (s, 1H), 4.78-4.72 (m, 2H), 4.43 (d, J=4.4 Hz, 2H), 3.94 (s,3H), 2.68 (s, 3H), 2.62 (s, 3H), 1.58 (d, J=6.4 Hz, 6H). LC-MS (m/z) 366(MH⁺); t_(R)=1.6 minutes (Method C).

Example 201:5-[2-(dimethylamino)-3-pyridyl]-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 29 from5-(2-(dimethylamino)pyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-methyl-1H-pyrazole-4-carbaldehyde. ¹H NMR (Chloroform-d, 600 MHz)δ 8.22 (dd, J=4.8, 1.9 Hz, 1H), 7.83 (dd, J=7.3, 1.9 Hz, 1H), 7.54 (s,1H), 7.40 (s, 1H), 6.87-6.82 (m, 2H), 4.77 (hept, J=6.6 Hz, 1H), 4.58(t, J=4.7 Hz, 1H), 4.33 (d, J=5.0 Hz, 2H), 3.93 (s, 3H), 2.73 (s, 6H),2.64 (s, 3H), 1.61 (d, J=6.6 Hz, 6H).

LC-MS (m/z) 405.6 (MH⁺); t_(R)=0.34 minutes (Method D).

Example 202:1-isopropyl-3-methyl-N-((1-methyl-H-pyrazol-4-yl)methyl)-5-(4-methyloxazol-2-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

A mixture of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(100 mg, 0.28 mmol), 4-methyloxazole (46 mg, 0.55 mmol), XPHOS—Pd-G3((2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate) (12 mg, 0.014 mmol), t-BuOK (93 mg, 0.83 mmol) indimethylacetamide (5 mL) was stirred at 100° C. for 12 hours under N₂.The mixture was concentrated under vacuum. The residue was purified bypreparative TLC (SiO₂, Petroleum ether/ethyl acetate=0:1) andpreparative HPLC to afford1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(4-methyloxazol-2-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz): δ 7.58 (s, 1H), 7.53 (s, 1H), 7.45 (s,1H), 7.34 (s, 1H), 4.77-4.67 (m, 1H), 4.58 (brs, 1H), 4.44 (d, J=4.8 Hz,2H), 3.94 (s, 3H), 2.68 (s, 3H), 2.29 (s, 3H), 1.58 (d, J=6.8 Hz, 6H).LC-MS (m/z) 366.1 (MH⁺); t_(R)=1.74 minutes (Method C).

Example 203:1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(4-methyl-1,2,4-triazol-3-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for example 195 from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 4-methyl-4H-1,2,4-triazole.

¹H NMR (CDCl₃ 400 MHz): δ 8.18 (s, 1H), 7.56 (s, 1H), 7.55 (s, 1H), 7.48(s, 1H), 4.78-4.71 (m, 1H), 4.60 (brs, 1H), 4.44 (d, J=4.4 Hz, 2H), 4.23(s, 3H), 3.93 (s, 3H), 2.60 (s, 3H), 1.59 (d, J=6.4 Hz, 6H) LC-MS (m/z)366.1 (MH⁺); t_(R)=1.65 minutes (Method B).

In Vitro Testing PDE1 Inhibition Assay

PDE1A, PDE1B and PDE1C assays were performed as follows: the assays wasperformed in 60 μL samples containing a fixed amount of the PDE1 enzyme(sufficient to convert 20-25% of the cyclic nucleotide substrate), abuffer (50 mM HEPES pH 7.6; 10 mM MgCl₂; 0.02% Tween20), 0.1 mg/ml BSA,15 nM tritium labelled cAMP and varying amounts of inhibitors. Reactionswere initiated by addition of the cyclic nucleotide substrate, andreactions were allowed to proceed for 1 hr at room temperature beforebeing terminated through mixing with 20 μL (0.2 mg) yttrium silicate SPAbeads (PerkinElmer). The beads were allowed to settle for 1 hr in thedark before the plates were counted in a Wallac 1450 Microbeta counter.The measured signals were converted to activity relative to anuninhibited control (100%) and IC₅₀ values were calculated using XIFit(model 205, IDBS).

1-19. (canceled)
 20. A compound:

or a pharmaceutically acceptable salt thereof.
 21. The compound of claim20:


22. A pharmaceutically acceptable salt of the compound of claim
 20. 23.A pharmaceutical composition comprising the compound of claim 20, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient.
 24. A compound:

or a pharmaceutically acceptable salt thereof.
 25. The compound of claim24:


26. A pharmaceutically acceptable salt of the compound of claim
 24. 27.A pharmaceutical composition comprising the compound of claim 24, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient.
 28. A compound:

or a pharmaceutically acceptable salt thereof.
 29. The compound of claim28:


30. A pharmaceutically acceptable salt of the compound of claim
 28. 31.A pharmaceutical composition comprising the compound of claim 28, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient.
 32. A compound:

or a pharmaceutically acceptable salt thereof.
 33. The compound of claim32:


34. A pharmaceutically acceptable salt of the compound of claim
 32. 35.A pharmaceutical composition comprising the compound of claim 32, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient. 36-38. (canceled)